Total synthesis of (-)-epimyrtine by a gold-catalyzed hydroamination approach

Article abstract of DOI:10.3762/bjoc.9.242

A new approach to the total synthesis of (-)-epimyrtine has been developed from D-alanine. The key step to access the enantiopure pyridone intermediate was achieved by a gold-mediated cyclization. Finally, various transformations afforded the natural prod

Full text of DOI:10.3762/bjoc.9.242

Total synthesis of (−)-epimyrtine by a gold-catalyzed
hydroamination approach
Thi Thanh Huyen Trinh, Khanh Hung Nguyen, Patricia de Aguiar Amaral
and Nicolas Gouault*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2042–2047.
Equipe PNSCM, UMR6226, Université de Rennes 1, 2 avenue du Pr
Léon Bernard, 35043 Rennes Cedex, France
doi:10.3762/bjoc.9.242
Received: 01 July 2013
Email:
Accepted: 24 September 2013
Published: 09 October 2013
Nicolas Gouault* - nicolas.gouault@univ-rennes1.fr
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
Keywords:
epimyrtine; gold; gold catalysis; heterocycles; hydroamination;
quinolizidine alkaloid; total synthesis
Guest Editor: F. D. Toste
© 2013 Trinh et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A new approach to the total synthesis of (−)-epimyrtine has been developed from D-alanine. The key step to access the enantiopure
pyridone intermediate was achieved by a gold-mediated cyclization. Finally, various transformations afforded the natural product in
a few steps and good overall yield.
Findings
(−)-Epimyrtine, isolated from Vaccinium myrtillus (Ericaceae) Mannich reaction [8], and the iminium ion cascade reaction
[1,2], is a quinolizidine alkaloid. This alkaloid family exhibits [9,10]. More efficient, convenient and highly stereoselective
potential pharmacological properties such as anticancer, synthetic routes are still being sought after. In the past decades,
antibacterial, antiviral and anti-inflammation activities [3-5]. gold catalysis has emerged as an important tool in a plethora of
This alkaloid has been a target of interest for synthetic chemists fields of synthetic organic chemistry, and after methodological
because of its structural simplicity among the family of quino- investigations [11-16], the good functional group compatibility
lizidine structures. Since it has been isolated, numerous total of gold catalysts renders gold catalysis a straightforward
syntheses of this alkaloid in racemic form have been reported in protocol in the realm of the synthesis of natural products
the literature. However, only a few asymmetric syntheses of [17,18].
(−)-epimyrtine have been described to date including the
intramolecular allylsilane N-acyliminium ion cyclization [6], the Herein we report a short total synthesis of (−)-epimyrtine
organocatalytic aza-Michael reaction [7], the intramolecular employing an alternative strategy by using a gold(I)-catalyzed
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hydroamination of a β-aminoynone as the key step. Actually, Wolff rearrangement was then carried out by using silver nitrate
cyclization of enantiopure α and β-aminoynones was success- in THF to give the intermediate ketene which was trapped with
fully used in our group to access pyrrolidinone and pyridone N,O-dimethylhydroxylamine to provide the corresponding
heterocycles via a gold-mediated approach [19,20]. The use of Weinreb amide 1 in 84% yield over two steps. In the next step,
β-aminoynone intermediates for the synthesis of 2,3-dihydro- the Weinreb amide 1 was added to a solution of O-protected
pyridones was recently developed by Georg [21] (Scheme 1). 1-hexynol lithium acetylide to furnish the β-aminoynone 2 with
This strategy involves the in situ deprotection of the amine a yield of 71%. With this key building block in hand, efforts
function to permit the cyclization by Michael addition. were directed toward the gold-mediated intramolecular
However, in some instances partial racemization of the reaction hydroamination for the construction of the chiral pyridone inter-
products was observed [22].
mediate 3. For this, PPh3AuSbF6 generated in situ from a
5 mol % mixture of PPh3AuCl and AgSbF6, in 1,2-
Here, one major advantage of gold catalysis is the use of very dichloroethane afforded the desired pyridone 3. These condi-
mild conditions for the cyclization, thereby avoiding any racem- tions, selected in our previous work, represent a good compro-
ization and obtaining N-protected compounds which may be mise in terms of reaction time, yield and cost of the catalyst. As
useful for further transformations. In order to illustrate the effi- an example, lower catalyst loading (1 mol %) does not affect
ciency of our method, we were interested in extending this the yield but lowers the reaction speed of the cyclization. A
methodology to quinolizidine privileged structures.
5-exo-dig product was not observed, presumably as a result of
electronic strain. The reaction was completed in 2 hours at
Our retrosynthetic analysis is shown in Scheme 2. We expected 40 °C to afford 3 in good yield (78%).
that the good side-chain functionality tolerance of the gold cata-
lyst could easily provide chiral dihydropyridone from the Reduction and deprotection of 3 by means of H2 (1 atm) in the
corresponding β-aminoynone in a 6-endo-dig selective cycliza- presence of Pd/C for 48 h afforded stereospecifically the corres-
tion process. The β-aminoynone could be stereoselectively ponding piperidone 4 in 80% yield. Subsequent bromination
prepared in two steps from N-Boc-D-alanine.
with CBr4 in the presence of PPh3 (Appel reaction) gave 5 in
84% yield. Finally, deprotection with 1 M SnCl4 in
Preparation of the β-aminoynone 2 began with the Arndt–Eistert dichloromethane then neutralization by using K2CO3 afforded
homologation [23] of N-Boc-protected D-alanine (Scheme 3). the final product (−)-epimyritine in a 80% yield.
Thus, the N-Boc-D-alanine was treated with isobutyl chlorofor-
mate at 0 °C in THF/diethyl ether followed by the addition of N-Cbz compound was also tested. In this case, the cyclization
diazomethane to afford the corresponding diazoketone. The occurred in similar conditions as described for the N-Boc-
Scheme 1: Previously reported approach from β-aminoynones for the synthesis of pyridones.
Scheme 2: Retrosynthetic analysis of (−)-epimyrtine.
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Scheme 3: Synthesis of (−)-epimyrtine.
protected compound and resulted in a good yield (81%). Yet, Experimental
under the catalytic hydrogenolytic conditions as described All reagents of high quality were purchased from commercial
above (H2, 1 atm, 10% Pd/C, rt, 48 h) only deprotection of the suppliers and used without further purification. All reactions
nitrogen occured, while the desired benzyl ether cleavage and requiring anhydrous conditions were performed under an argon
pyridine reduction were unsuccessful. Increase of the pressure atmosphere by using oven-dried glassware. 1,2-DCE and THF
to 5 atm or replacement of Pd/C with Pd(OH)2 (Pearlman’s were distilled from CaH2 and Na/benzophenone, respectively.
catalyst) did also not result in the obtainment of the desired 1H and 13C NMR were recorded at 500 or 300 and 125 or
product.
75 MHz respectively, by using CDCl3 (and TMS as internal
standard). Chemical shifts, δ values are given in parts per
The natural product (−)-epimyritine was thus obtained over million (ppm), coupling constants (J) are given in Hertz (Hz),
6 steps in a 25% overall yield starting from N-Boc-D-alanine. and multiplicity of signals are reported as follows: s, singlet; d,
The spectroscopic data and optical rotation are in agreement doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; app,
with the literature [6].
apparent. Thin-layer chromatography was performed by using
pre-coated silica gel plates (0.2 mm thickness).
Conclusion
In conclusion, we have achieved the asymmetric total synthesis
of (−)- epimyrtine in six steps and with a good overall yield. We
have demonstrated in this work that this natural product is
easily accessible from D-alanine by a gold-mediated intramole-
cular hydroamination in a unique 6-endo-dig process. The ap-
proach provides a straightforward tool for synthetic applica-
tions toward quinolizidines and indolizidines.
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To a solution of 6-benzyloxyhex-1-yne (2.44 g, 12.9 mmol, 52.1, 42.7, 35.8, 29.4, 28.1, 24.7, 16.5; HRMS–ESI+ (m/z):
4 equiv) in 10 mL of dry THF was added dropwise a solution of [M + Na]+ calcd for C22H31NO4Na, 396.2151; found,
n-BuLi (5 mL, 12.5 mmol, 3.8 equiv) at −78 °C under argon 396.2153.
atmosphere. The reaction mixture was stirred for 45 min at
−78 °C. Then, a solution of Weinreb amide 1 (800 mg,
3.3 mmol, 1 equiv) in 8 mL of dry THF was added dropwise at
−78 °C. The reaction was stirred for 1 h. The reaction was
warmed to −20 °C and stirred for 2 h. The reaction was
quenched with a solution of 1 M NaH2PO4 (50 mL). The
aqueous layer was extracted with ethyl acetate. The organic
layer was washed with brine, dried over Na2SO4, concentrated Pd/C (45 wt %) was added to a solution of 3 (585.7 mg,
under reduced pressure, and purified by silica gel column chro- 1.57 mmol, 1 equiv) in 12 mL of MeOH, and the mixture was
matography by using petroleum ether/ethyl acetate (9:1) as an stirred under hydrogen atmosphere (1 atm) for 48 h at room
eluent to give pure 2 as a yellow oil (250 mg, 71%). Rf 0.3 temperature. The mixture was filtered through a pad of celite®,
(petroleum ether/ethyl acetate, 8:2). [α]D25 +2.3 (c 1.7, CHCl3); concentrated and purified by silica gel column chromatography
1H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.8 Hz, 3H), 1.43 (s, eluting with petroleum ether/ethyl acetate to give 4 as a yellow
9H), 1.69–1.74 (m, 4H), 2.40 (t, J = 6.7 Hz, 2H), 2.66 (ABX oil (360 mg, 80%). Rf 0.25 (petroleum ether/ethyl acetate, 5:5).
system, JAB = 16.2 Hz, JBX = 6.2 Hz, 1H), 2.80 (ABX system, [α]D25 −21.9 (c 1.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ
JAB = 16.2 Hz, JAX = 5.3 Hz, 1H), 3.50 (t, J = 5.8 Hz, 2H), 1.28 (d, J = 5.0 Hz, 3H), 1.35–1.42 (m, 3H), 1.49 (s, 9H),
4.05–4.14 (m, 1H), 4.50 (s, 2H), 4.74 (brs, 1H), 7.29–7.35 (m, 1.57–1.62 (m, 4H) 2.28 (ddd, J = 14.9 Hz, J = 3.8 Hz, J = 1.6
5H); 13C NMR (125 MHz, CDCl3) δ 186.0, 155.0, 138.3, Hz, 1H), 2.34 (dt, J = 15.0 Hz, J = 1.8 Hz, 1H), 2.68 (dd, J =
128.3, 127.6, 127.5, 106.4, 94.8, 81.1, 72.9, 69.4, 51.3, 15.0 Hz, J = 7.6 Hz, 1H), 2.72 (dd, J = 14.9 Hz, J = 7.5 Hz,
43.3, 28.8, 28.3, 24.5, 18.7; HRMS–ESI+ (m/z): 1H), 3.64 (brs, 2H), 4.61–4.62 (m, 1H), 4.70 (brs, 1H); 13C
[M + Na]+ calcd for C22H31NO4Na, 396.2151; found, NMR (125 MHz, CDCl3) δ 208.7, 154.9, 80.3, 62.6, 52.5, 48.4,
396.2153.
45.5, 43.8, 36.6, 32.2, 28.4, 23.0, 22.7; HRMS–ESI+ (m/z):
[M + Na]+ calcd for C15H27NO4Na, 308.1838, found,
308.1838.
To a solution of 2 (838 mg, 2.2 mmol, 1 equiv) in 15 mL of
anhydrous 1,2-dichloroethane was added PPh3AuCl (55 mg, CBr4 (674.5 mg, 2 mmol, 2 equiv) and PPh3 (586.8 mg,
0.11 mmol, 5 mol %) and AgSbF6 (38 mg, 0.11 mmol, 2.2 mmol, 2.2 equiv) were added to a solution of 4 (290 mg,
5 mol %) under argon atmosphere. The mixture was stirred for 1 mmol, 1 equiv) in 6 mL of dichloromethane at 0 °C. The mix-
2 h at 40 °C. The reaction was cooled to room temperature and ture was stirred at 0 °C for 15 min. Then, the reaction was
diluted with ether. The organic phase was filtered through a pad warmed to room temperature and stirred for 1 h. The solvent
of Celite®, concentrated under reduced pressure, purified by was removed under reduced pressure and the mixture was puri-
silica gel column chromatography, and eluted with petroleum fied by silica gel column chromatography by using
ether/ethyl acetate (9:1) to give 3 as a yellow oil (78%). Rf 0.25 dichloromethane/ethyl acetate (95:5) as eluent to give 5 as a
(petroleum ether/ethyl acetate, 8:2). [α]D25 −226.9 (c 1.6, yellow oil (293 mg, 84%). Rf 0.6 (dichloromethane/ethyl
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.25 (d, J = 6.8 Hz, acetate, 9:1). [α]D25 −19.1 (c 1.1, CHCl3); 1H NMR (500 MHz,
3H), 1.52 (s, 9H), 1.55–1.67 (m, 4H), 2.23 (dt, J = 16.9 Hz, J = CDCl3) δ 1.27 (d, J = 7.0 Hz, 3H), 1.47–1.56 (m, 12H),
1.5 Hz, 1H), 2.31 (ddd, J = 14.7 Hz, J = 8.5 Hz, J = 6.0 Hz, 1.61–1.67 (m, 1H), 1.83–1.91 (m, 2H), 2.28 (ddd, J = 14.8 Hz,
1H), 2.81 (dd, J = 16.9 Hz, J = 6.2 Hz, 1H), 3.07 (ddd, J = 14.6 J = 3.5 Hz, J = 1.5 Hz, 1H), 2.32 (dt, J = 15.9 Hz, J = 1.7 Hz,
Hz, J = 9.3 Hz, J = 5.2 Hz, 1H), 3.47 (t, J = 6.2 Hz, 2H), 4.49 1H), 2.69 (dd, J = 15.3 Hz, J = 7.7 Hz, 1H), 2.73 (dd, J = 15.1
(s, 2H), 4.78 (app quintd, J = 6.6 Hz, J = 1.4 Hz, 1H), 5.36 (s, Hz, J = 7.9 Hz, 1H), 3.40 (td, J = 6.6 Hz, J = 1.5 Hz, 2H),
1H), 7.30–7.36 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 193.7, 4.60–4.63 (m, 1H), 4.73 (brs, 1H); 13C NMR (125 MHz,
158.3, 152.1, 138.5, 128.4, 127.6, 127.6, 111.1, 82.9, 72.9, 69.8, CDCl3) δ 208.5, 154.8, 80.4, 52.4, 48.5, 45.5, 43.9, 36.1, 33.5,
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Beilstein J. Org. Chem. 2013, 9, 2042–2047.
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To a solution of 5 (263 mg, 0.75 mmol, 1 equiv) in 5 mL of
CH2Cl2 under argon atmosphere was added a solution of 1 M
SnCl4 in CH2Cl2 (3.8 mL, 5.0 equiv). The reaction was stirred
at room temperature for 3 h. The solvent was removed under
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chromatography eluting with dichloromethane/MeOH (9:1) to
give (−)-epimyrtine as a yellow oil (102 mg, yield 80%). Rf 0.3
(dichloromethane/MeOH, 9:1). [α]D25 −16.9 (c 1.2, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 1.20 (d, J = 5.6 Hz, 3H), 1.23–1.32
(m, 1H), 1.39–1.45 (m, 1H), 1.59–1.69 (m, 2H), 1.70–1.78 (m,
2H), 1.83 (td, J = 11.2 Hz, J = 2.1 Hz, 1H), 2.17 (brt, J = 11.1
Hz, 1H), 2.22–2.32 (m, 2H), 2.27–2.32 (m, 2H), 2.34–2.45 (m,
3H), 3.32 (d, J = 11.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
208.4, 62.0, 59.3, 51.0, 49.8, 48.7, 34.2, 25.9, 23.9, 20.7;
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Supporting Information
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Supporting Information File 1
Spectra of new compounds.
23.Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. B 1935, 68, 200–208.
doi:10.1002/cber.19350680142
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-242-S1.pdf]
Acknowledgements
We thank the Program Ciências Sem Fronteiras (Brazil) for
supporting Patricia de Aguiar Amaral in a post-doctoral pos-
ition.
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