Synthesis of (±)-trans-indolizidine-8-carboxylic acid

Article abstract of DOI:10.1055/s-0030-1259558

A facile synthesis of a novel amino acid, trans-indolizidine-8-carboxylic acid, is described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259558

LETTER
663
Synthesis of (±)-trans-Indolizidine-8-carboxylic Acid
S
W
ynthesis of
(
±
)-trans-In
e
dolizidine
-
n
8-carboxylic
-
A
cid Hua Chiou,* Yi-Huei Lin, Yu-Kai Gao
Department of Chemistry, National Chung Hsing University, Taichung, 402 Taiwan, R.O.C.
Fax +886(4)22862547; E-mail: wchiou@dragon.nchu.edu.tw
Received 19 December 2010
ketone 3 was able to be achieved by direct treatment of the
crude product in a basic methanol solution, affording 71%
combined yield over two steps.
Abstract: A facile synthesis of a novel amino acid, trans-indolizi-
dine-8-carboxylic acid, is described.
Key words: amino acids, bicyclic compounds, heterocycles,
hydroformylation, tandem reactions
Indolizidines are very important compounds because of
their presence in many natural alkaloids, pharmaceuticals,
and synthetic useful intermediates. In addition, rigidified
amino acids, linking its nitrogen to its carbon backbone,
are proven to be a useful concept in rational design of pep-
1
,2
tidomimetics. In the course of our interest in this field,
a rapid and convenient synthesis of indolizidine-8-car-
boxylic acid is required. However, to the best of our
knowledge, there is no reported method to synthesize this
amino acid. Herein we describe a facile synthesis of this
compound using our recently developed tandem Rh-cata-
lyzed hydroformylation–double cyclization reactions.3
Figure 1 The ROESY correlation and calculated geometry of (E)-
enol acetate 2, calculated by DFT at the level of B3LYP/6-31G* and
verified by vibrational analysis (see the Supporting Information)
Our syntheses commenced with hydroformylation on N-
allylamides of 4-alkynoic acid 1 (Scheme 1), readily4
available from the corresponding acid and allylamine.
The key reaction was carried out using a low loading of
In order to functionalize the arylketone substituent at C-8
of the indolizidinone moiety, the ketone group needed to
be oxidized to an ester group for the subsequent transfor-
5
,6
Rh-BIPHEPHOS (0.5 mol%) at 60 °C under 4 atm of
CO and H (1:1) in acetic acid, providing a single product
2
9
mations. Various Baeyer–Villiger oxidation conditions
in 83% isolated yield. After hydroformylation of 1 was
complete, spontaneous intramolecular addition of the
amide moiety on the resulting aldehyde led the formation
of hemiamidal. In the presence of acid, dehydration to N-
acyliminium followed by intramolecular addition of the 4-
methoxyphenyl-acetylene moiety furnished the indolizi-
dine moiety. Subsequent addition with a solvent molecule
of ketone 3 were investigated, including MCPBA in a
chlorinated solvent or in buffer solutions, UHP (urea-
hydrogen peroxide)–TFAA in buffer solutions, and
(
TMSO) with different Lewis acids. Unfortunately, for-
2
mation of the desired ester was not observed even under
10
forcing conditions. Gratifying, Uneyama’s protocol, us-
ing 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a cosol-
vent in dichloromethane and a phosphate buffer solution,
brought about the formation of desired ester 4, confirmed
by appearance of a new d = 171.5 ppm peak and disap-
pearance of the ketone peak. Moreover, a large shift of a
7
afforded enol acetate 2 as the product. The configuration
of enol acetate 2 was clearly identified by ROESY spec-
troscopy, showing clearly a strong correlation between the
phenyl protons d = 7.28 (H-2¢) ppm and the bridgehead
proton d = 4.18 (H-8a) ppm. The distance of these two
protons calculated by DFT was 3.017 Å, which also sup-
ported the experimental observation (Figure 1).
1
doublet peak from d = 7.93 to 6.97 ppm in the H NMR
spectra implied that the oxygen atom has been inserted at
the aromatic side, rather than at the alkyl side.
Exposure of enol acetate 2 in a basic methanol solution at
room temperature produced aryl ketone 3 in 81% yield. A
H- H coupling constant of 10.8 Hz was observed in both
Direct treatment of lactam 4 in basic conditions led to a
messy mixture, implying the indolizidinone was vulnera-
ble in the basic conditions. Thus, selective reduction of
lactam was carried out with BH ·SMe , affording amine 5
in 72% yield. Transesterification to methyl ester 6 was
carried out in basic methanol solution, yielding a yellow-
ish product in 82% yield. Acidic hydrolysis of methyl
ester 6 followed by treatment with propylene oxide to
neutralize excess hydrogen chloride gave trans-indolizi-
dine-8-carboxylic acid (7) in 99% yield.
1
1
peaks of d = 3.30 and 3.83 ppm, which assigned as H-8
3
2
and H-8a, respectively. The larger coupling constant indi-
8
cated a trans arrangement between H-8 and H-8a. In fact,
SYNLETT 2011, No. 5, pp 0663–0664
x
x.
x
x.
2
0
1
1
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1259558; Art ID: W20010ST
©
Georg Thieme Verlag Stuttgart · New York

6
64
W.-H. Chiou et al.
LETTER
OMe
MeO
OMe
AcO
O
H
O
O
H
(
a)
(b)
81%
(c)
MeO
HO
H
N
83%
N
N
66%
N
O
O
O
O
1
2
3
4
O
O
H
MeO
O
H
O
H
(
d)
(e)
82%
(f)
MeO
72%
N
N
99%
N
5
6
7
Scheme 1 Synthesis of trans-indolizidine-8-carboxylic acid. Reagents and conditions: (a) Rh(acac)(CO) (0.5 mol%), BIPHEPHOS (1.0
2
mol%), CO (2 atm), H (2 atm), PTSA (10 mol%), AcOH, 60 °C 18 h; (b) K CO (25 mol%), MeOH, r.t., overnight; (c) MCPBA (3.0 equiv),
2
2
3
HFIP/phosphate buffer, 40 °C, overnight; (d) BH ·SMe (4 equiv), 0 °C to r.t., 2 h; (e) K CO (1.1 equiv), MeOH, r.t., overnight; (f) aq HCl,
3
2
2
3
reflux, 2 h; propylene oxide, EtOH, reflux.
4
In conclusion, we utilize a novel domino reaction, alkyne-
mediated Rh-catalyzed hydroformylation tandem double
cyclization reaction, to synthesize to a novel amino acid,
trans-indolizidine-8-carboxylic acid (7) in 26% overall
yield. Application of the amino acid in the research of
peptidomimetics and extension of this methodology to-
ward other natural products of interest are currently under
way and will be reported in the future.
three times. Amide 1 (730 mg, 3.0 mmol, 1.00 equiv) and
PTSA (57 mg, 0.3 mmol, 10 mol%) were placed in a 100 mL
flask. The catalyst solution was transferred to the reaction
flask containing the substrate by a pipette, and the total
volume was adjusted to 60 mL with AcOH. The reaction
flask was placed in a 300 mL stainless steel autoclave and
then was pressurized with CO (2 atm) followed by H (2
2
atm). The reaction mixture was stirred at 60 °C for 16–20 h.
Upon completion of the reaction, the gas was carefully
released in a good ventilated hood, and the reaction mixture
was concentrated under reduced pressure to give a crude
residue. The residue was partitioned with CH Cl (20 mL)
and aq NaHCO (10 mL). After separation of the organic
layer, the aqueous layer was extracted with CH Cl (3 × 10
mL). The combined organic layers were washed with brine
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
2
2
3
2
2
(
10 mL), dried over anhyd Na SO , and then concentrated
Acknowledgment
2 4
under reduced pressure to give the crude product. The crude
product was purified by flash chromatography on silica gel
using MeOH–CH Cl as the eluant to give the product in
We thank the National Science Council, Taiwan (NSC97-2113-M-
0
05-004 and NSC98-2119-M-005-004-MY3), and the Instrument
2
2
Center of National Chung Hsing University for support of this
research.
8
3% yield as a light yellow oil. R = 0.45 (MeOH–
f
1
CH Cl = 1:9). H NMR (600 MHz, 25 °C, CDCl ): d = 1.35
2
2
3
(
1
dq, J = 5.4, 10.8 Hz, 1 H, H-1), 1.57–1.63 (m, 1 H, H-2),
.63–1.69 (m, 1 H, H-1), 1.76–1.84 (m, 1 H, H-2), 2.13 (s, 3
H, OCCH ), 2.24 (ddd, J = 3.6, 15.0, 15.0 Hz, 1 H, H-7),
References and Notes
3
2
.36 (ddd, J = 4.2, 15.6, 15.6 Hz, 1 H, H-6), 2.52 (ddd,
(
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(
(
(
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3
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3
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3
+
+
[M + H] calcd for C H NO : 316.1549; found: 316.1541
18 22 4
(
D = 2.5 ppm).
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(
8) The results of DFT calculations for ketone trans-3 and cis-3
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than cis-3 by 2.1 kcal/mol.
(
(
2066.
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(
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oxoindolizidine (2)
Rh(acac)(CO) (3.9 mg, 15.0 mmol, 0.5 mol%) and
2
(
BIPHEPHOS (23.4 mg, 30 mmol, 1.0 mol%) were dissolved
in AcOH (1 mL) under nitrogen. The resulting catalyst
solution was degassed by a freeze–thaw procedure at least
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