Achiral auxiliary-assisted chiral transfer via microwave-accelerated aza-Claisen rearrangement: A short synthesis of (+)-1-hydroxyquinolizidinone

Article abstract of DOI:10.1016/j.tetlet.2012.06.073

A short and efficient synthesis of (+)-1-hydroxyquinolizidinone as an advanced core intermediate for the syntheses of (+)-epiquinamide, (+)-homopumiliotoxin, and (+)-lupinine is described. The key feature of our strategy includes a sequential chiral transfer using an achiral phenylsulfide auxiliary via microwave-accelerated aza-Claisen rearrangement of the unexplored N-thiophenoxyacetyl-α-vinyl piperidine substrate and the oxone-induced transannulation.

Full text of DOI:10.1016/j.tetlet.2012.06.073

Tetrahedron Letters 53 (2012) 4813–4815
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Achiral auxiliary-assisted chiral transfer via microwave-accelerated
aza-Claisen rearrangement: a short synthesis of (+)-1-hydroxyquinolizidinone
Jaehoon Sim a, Hwayoung Yun a, Jong-Wha Jung b, Sujin Lee a, Nam-Jung Kim a, Young-Ger Suh a,
⇑
a College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and efficient synthesis of (+)-1-hydroxyquinolizidinone as an advanced core intermediate for the
syntheses of (+)-epiquinamide, (+)-homopumiliotoxin, and (+)-lupinine is described. The key feature of
our strategy includes a sequential chiral transfer using an achiral phenylsulfide auxiliary via micro-
wave-accelerated aza-Claisen rearrangement of the unexplored N-thiophenoxyacetyl-a-vinyl piperidine
substrate and the oxone-induced transannulation.
Received 23 April 2012
Revised 11 June 2012
Accepted 15 June 2012
Available online 28 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
(+)-1-Hydroxyquinolizidinone
Quinolizidine alkaloid
aza-Claisen rearrangement
Transannulation
Achiral auxiliary
The quinolizidine alkaloids are considered attractive synthetic
targets by both organic and medicinal chemists because of their
structural and biological diversity.1 Epiquinamide was isolated in
2003 from the Ecuadoran poison frog Epipedobates tricolor,2 but
further studies on the biological activities were limited due to its
We previously reported asymmetric total syntheses of natural
alkaloids employing azacycle ring-expansion induced by aza-
Claisen rearrangement (ACR).7 In addition, we have recently ex-
plored an extension of our ring-expansion strategy, which involved
chiral transfer through the thiophenyl-substituted N-acyl moiety
of the ACR precursor. Especially, the thiophenyl group served as
an achiral auxiliary, which realized a sequential chiral transfer
strategy. The thiophenyl group initially provided a 1,4-chiral trans-
fer via ACR and then induced a tandem epoxidation-transannula-
tion in a remarkably stereoselective manner. We were able to
apply this unprecedented procedure to the asymmetric synthesis
of quinolizidine alkaloid. Herein, we report an achiral auxiliary-as-
sisted chiral transfer via ACR and its application to a concise syn-
thesis of (+)-1-hydroxyquinolizidinone 1, a core and advanced
intermediate for the syntheses of (+)-epiquinamide, (+)-homop-
umiliotoxin 223G, and (+)-lupinine (Fig. 1).8
paucity from natural sources (240 lg from 183 frogs). Homopumi-
liotoxin 223G was first discovered in 1987 in the Panamanian poi-
son frog Dendrobates pumilio,3 and asymmetric total syntheses of
this alkaloid were completed by only two research groups4 in spite
of its unique structure. Lupin alkaloids, a large family of quinolizi-
dine alkaloids, are known to have a wide range of biological activ-
ities including anticholinesterase activity, activation of nicotinic
receptor, and antimicrobial activity.5 Lupinine is considered a rep-
resentative of the Lupin alkaloids and is of interest to synthetic
chemists due to its structural simplicity.6 Thus, we have recently
worked toward development of efficient synthetic routes for the
quinolizidine alkaloids.
Our retrosynthetic approach to (+)-1-hydroxyquinolizidinone 1
is illustrated in Scheme 1. The key part of our unique synthesis
includes the ACR-induced stereoselective ring expansion of N-thio-
OH
OH
H
N
phenoxyacetyl-a-vinyl piperidine (4) and the substrate-controlled
NHAc
OH
H
N
H
N
H
N
O
OH
H
OH
H
(+)-Epiquinamide (+)-Homopumiliotoxin 223G (+)-Lupinine (+)-1-Hydroxyquinolizidinone 1
Figure 1. Representative quinolizidine alkaloids.
H
N
N
SPh
SPh
N
N
SO2Ph
O
O
O
O
2
1
3
4
⇑
Corresponding author.
E-mail address: ygsuh@snu.ac.kr (Y.-G. Suh).
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.073

4814
J. Sim et al. / Tetrahedron Letters 53 (2012) 4813–4815
stereoselective transannulation of the resulting 10-membered lac-
tam intermediate 3. Through this sequence, the steroselective for-
mations of the new stereocenters would be achieved by the
sequential chiral transfers, which are assisted by the phenyl sulfide
auxiliary. The final quinolizidinone 1 could be obtained from 2 by
the reductive removal of the benzenesulfonyl group. The vinylpi-
peridine 4 was expected to be readily accessible from the commer-
cially available carboxylic acid 5.
sulfonyl group.14 Finally, (+)-1-hydroxyquinolizidinone 1 could be
obtained by desulfonylation of 2 with 6% Na/Hg in the presence of
boric acid.15 The structure of synthetic 1 was confirmed by com-
parison of the spectral data with the reported data (1H NMR, 13C
NMR, IR, HR-MS and optical rotation).7a,10
CO2H
Boc
ref. 12
1. TMSOTf , 2,6-lutidine, CH2Cl2, 0°C
The synthesis of (+)-1-hydroxyquinolizidinone 1 was com-
menced with the intensive examination of the ACR-induced ring-
expansion of 4 as summarized in Table 1. Our initial attempt to
perform the ACR-induced ring-expansion of 4 under our standard
reaction conditions7 was unfortunately not successful (entry 1).
Poor stereoselectivity and unsatisfactory yield were observed.
The low stereoselectivity was likely due to the epimerization of
the initially established chiral center of the ring-expansion prod-
ucts 3 under the harsh reaction conditions, which included excess
base and a long reaction time.9 Reductions in the amount of base
and in the reaction time (entries 2–3) slightly improved the stere-
oselectivity, as we had anticipated. Replacing LHMDS with i-
PrMgCl slightly increased the conversion yield up to 22% (entry
4).7b Finally, we were able to obtain a satisfactory stereoselectivity
and chemical yield by accelerating the ACR utilizing a micro-
wave.10 Microwave irradiation enhanced the reaction rate of ACR
and consequently decreased reaction time, which resulted in the
excellent stereoselectivity (1:37) and chemical yield (83%) (entry
6). The short reaction time provided the high stereoselectivity
but decreased the conversion yield (entry 7). To the best of our
N
6
N
2. 7, EDCI, HOBt, NMM, CH2Cl2
Boc
62% for 2 steps
5
O
OXONE®
i-PrMgCl, MW(250W)
H
NH
O
N
N
SPh
SPh
MeOH/H2O
70%
toluene, 200°C
83%
SPh
O
4
O
3
OH
OH
H
N
H
N
6% Na/Hg, B(OH)3
HO2C
SPh
7
MeOH
78%
SO2Ph
O
2
O
(+)-hydroxyquinolizidinone 1
Scheme 2. Synthesis of (+)-1-hydroxyquinolizidinone 1.
In conclusion, the synthesis of (+)-1-hydroxyquinolizidinone, a
core and advanced intermediate for the synthesis of (+)-epiquin-
amide, (+)-homopumiliotoxin 223G, and (+)-lupinine, was
accomplished in five steps and with an overall yield of 28% from
the known 2-vinylpiperidine 6. The key part of the synthesis in-
volves the microwave-accelerated ACR of N-thiophenoxyacetyl-
knowledge, ACR of the
ported previously.
a-thio-substituted amide has not been re-
a-vinyl piperidine and the oxone-induced transannulation of
the 10-membered lactam intermediate. In particular, an unprec-
edented chiral transfer during the ACR utilizing the achiral phe-
nyl sulfide auxiliary is reported. Our unique synthetic approach
is expected to be utilized in the syntheses of quinolizidine
alkaloids.
Table 1
ACR of N-thiophenoxyacetyl-
a
-vinyl piperidine 4
N
condition
H
N
(S)
N
SPh
SPh
SPh
O
O
O
M
4
3
Acknowledgment
Entry Conditiona
Ratiob
(R:S)
Yieldc
(%)
This work was supported by the National Research Foundation
of Korea Grant funded by the Korean Government (MEST) (NRF-
C1ABA001-2010-0020428)
1
2
3
4
5
LHMDS(4.0 equiv), 140 °C, 48 h
LHMDS(2.0 equiv), 140 °C, 24 h
LHMDS(1.0 equiv), 140 °C, 24 h
i-PrMgCl(2.0 equiv), 140 °C, 24 h
LHMDS(1.0 equiv), MW(250 W), 200 °C,
1:1.5
1:2.0
1:4.2
1:2.8
1:35
64
19
10
22
10
References and notes
10 min
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Spande, T. F. J. Nat. Prod. 2000, 63, 1157–1159.
6
7
i-PrMgcl(1.0 equiv), MW(250 W), 200 °C,
10 min
i-PrMgcl(1.0 equiv), MW(250 W), 200 °C,
5 min
1:37
1:46
83
65
a
b
c
All reaction proceeded in toluene (0.05 M).
Ratios were detected by HPLC.
Isolated yield of mixtures.
5. (a) Kolak, U.; Hacıbekirog˘lu, I.; Bog˘a, M.; Özgökçe, F.; Ünal, M.; Choudhary, M.;
Ulubelen, A. Rec. Nat. Prod. 2011, 5, 309–313; (b) Coe, J. W.; Vetelino, M. G.;
Bashore, C. G.; Wirtz, M. C.; Brooks, P. R.; Arnold, E. P.; Lebel, L. A.; Fox, C. B.;
Sands, S. B.; Davis, T. I.; Schulz, D. W.; Rollema, H.; Tingley, F. D.; O’Neill, B. T.
Bioorg. Med. Chem. Lett. 2005, 15, 2974–2979; (c) Erdemoglu, N.; Ozkan, S.;
Tosun, F. Phytochem. Rev. 2007, 6, 197–201.
The ACR precursor 4 was prepared from the known (S)-2-vinyl-
N-Boc-piperidine 6, which was readily derived from commercially
available (S)-N-Boc-pipecolinic acid 5 (Scheme 211).12 Boc depro-
tection of 6 with TMSOTf in the presence of 2,6-lutidine and subse-
quent acylation of the resulting amine with 7 afforded amide 4 in
62% yield in 2 steps. The microwave-assisted ACR of amide 4 with
i-PrMgCl provided the ring-expanded lactam 3 in a yield of 83%.
During the ACR, the C-2 chirality of 6 was transferred to the thio-
phenyl-substituted stereocenter of 3. Lactam 3 was stereoselec-
tively transformed into the key quinolizidinone intermediate 2
by oxone-induced transannulation.13 Quinolizidinone 2 was effec-
tively obtained in a high yield and with a high stereoselectivity (>
12:1). The sulfide auxiliary was oxidized to the readily removable
6. (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 619–636; (b) Michael, J. P. Nat. Prod.
Rep. 1998, 15, 571–594.
7. (a) Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.; Koo, B.-A.; Kim, H.-S.
Angew. Chem. Int. Ed. 1999, 38, 3545–3547; (b) Paek, S.-M.; Kim, N.-J.; Shin, D.;
Jung, J.-K.; Jung, J.-W.; Chang, D.-J.; Moon, H.; Suh, Y.-G. Chem. Eur. J. 2010, 16,
4623–4628; (c) Lee, Y.-S.; Jung, J.-W.; Kim, S.-H.; Jung, J.-K.; Paek, S.-M.; Kim,
N.-J.; Chang, D.-J.; Lee, J.; Suh, Y.-G. Org. Lett. 2010, 12, 2040–2043; (d) Suh, Y.-
G.; Lee, Y.-S.; Kim, S.-H.; Jung, J.-K.; Yun, H.; Jang, J.; Kim, N.-J.; Jung, J.-W. Org.
Biomol. Chem. 2012, 10, 561–568.
8. (a) Huang, P.-Q.; Guo, Z.-Q.; Ruan, Y.-P. Org. Lett. 2006, 8, 1435–1438; (b)
Santos, L. S.; Mirabal-Gallardo, Y.; Shankaraiah, N.; Simirgiotis, M. J. Synthesis
2011, 1, 51–56.

J. Sim et al. / Tetrahedron Letters 53 (2012) 4813–4815
4815
9. To confirm the epimerization, intermediate 3 (a mixture of R and S in a 1:4.2
ratio) was retreated under the condition 3 of Table 1 (entry 3). As a result, we
could obtain the racemized product of 3 as a 1:1.3 mixture.
(2): ½a 2D0
ꢀ
+23.4 (c 0.150, CHCl3); FT-IR (thin film, neat) vmax 3419, 2940, 2860,
1H NMR (CDCl3, 400 MHz)
7.92 (t, 2H,
1634, 1469, 1446, 1308 cmꢁ1
;
d
J = 7.8 Hz), 7.60 (t, 1H, J = 7.4 Hz), 7.51 (t, 2H, J = 7.6 Hz), 4.54 (d, 1H,
J = 12.8 Hz), 4.19 (t, 1H, J = 6.9 Hz), 4.05 (m, 1H), 3.23 (s, 1H), 3.12 (d, 1H,
J = 11.2 Hz), 2.48 (m, 1H), 2.43–2.25 (m, 2H), 1.84 (m, 2H), 1.62 (d, 1H,
J = 12.7 Hz), 1.46–1.17 (m, 3H); 13C NMR (CDCl3, 100 MHz) d 160.2, 139.4,
133.6, 128.9, 128.9, 128.7, 128.7, 66.4, 63.7, 63.5, 43.6, 31.0, 27.0, 25.1, 24.1;
LR-MS (FAB+) m/z 310 (M+H+); HR-MS (FAB+) calcd for C15H20NO4S (M+H+)
10. (a) Gonda, J.; Martinková, M.; Zadrošová, A.; Šoteková, M.; Raschmanová, J.;
ˇ
Conka, P.; Gajdošíková, E.; Kappe, C. O. Tetrahedron Lett. 2007, 48, 6912–6915;
(b) Tymoshenko, D. O. Mini-Rev. Org. Chem. 2008, 5, 85–95; (c) Gajdošíková, E.;
ˇ
Martinková, M.; Gonda, J.; Conka, P. Molecules 2008, 13, 2837–2847.
11. Spectral data: (S)-2-(phenylthio)-1-(2-vinylpiperidin-1-yl)ethanone (4):
½
a 2D0
ꢀ
ꢁ93.6 (c 0.411, CHCl3); FT-IR (thin film, neat) vmax 2938, 2860, 1644,
310.1113; found 310.1114. (+)-Hydroxyquinolizidi none (1): ½a D20
ꢀ
+8.4 (c 0.0947,
1583, 1481, 1439, 1324 cmꢁ1 1H NMR (CDCl3, 400 MHz, mixture of rotamers)
;
CHCl3); FT-IR (thin film, neat) vmax 3390, 2936, 2860, 1602, 1485, 1446, 1421,
d 7.42 (d, 2H, J = 7.5 Hz), 7.27 (t, 2H, J = 7.6 Hz), 7.19 (t, 1H, J = 7.3 Hz), 5.72 (m,
1H), 5.29 (s), 5.21 (dd, 1H, J = 21.6, 10.5 Hz), 5.06 (d, 1H, J = 17.4 Hz), 4.56–4.41
(m, 1H), 3.77 (s, 2H), 3.66 (m, 2H), 3.18 (t, 0.5H, J = 12.16 Hz), 2.68 (t, 0.5H,
J = 12.46 Hz), 1.81–1.58 (m, 6H); 13C NMR (CDCl3, 100 MHz, mixture of
1363, 1339 cmꢁ1 1H NMR (CDCl3, 400 MHz) d 4.64 (d, 1H, J = 13.1 Hz), 3.76 (s,
;
1H), 3.65 (m, 1H), 3.10 (m, 1H), 2.50 (m, 1H), 2.35 (td, 1H, J = 13.0, 2.0 Hz), 2.24
(m,1H), 1.95–1.72 (m, 4H), 1.61 (d, 1H, J = 12.9 Hz), 1.49–1.25 (m,2H), 1.15 (m,
1H); 13C NMR (CDCl3, 100 MHz) d 168.5, 69.2, 63.7, 42.9, 31.5, 28.4, 26.7, 25.2,
24.3; LR-MS (FAB+) m/z 170 (M+H+); HR-MS (FAB+) calcd for C15H20NO4S
(M+H+) 170.1181; found 170.1176.
rotamers)
d 167.9, 167.3, 136.2, 136.0, 135.3, 130.1, 129.0, 126.8, 116.6,
116.4, 55.4, 50.2, 42.9, 42.8, 38.0, 37.0, 36.9, 29.8, 28.4, 26.2, 25.2, 19.4; LR-MS
(FAB+) m/z 262 (M+H+); HR-MS (FAB+) calcd for C15H20NOS (M+H+) 262.1266;
found 262.1263. (S,E)-3-(phenylthio)-3,4,7,8,9,10-hexahydroazecin-2(1H)-one
12. (a) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999, 121, 700–
709; (b) Lim, S. H.; Ma, S.; Beak, P. J. Org. Chem. 2001, 66, 9056–9062.
13. (a) Rodríguez, G.; Castedo, L.; Domínguez, D.; Saá, C. J. Org. Chem. 1999, 64,
877–883; (b) Zhu, W.; Ford, W. T. J. Org. Chem. 1991, 56, 7022–7026. The
plausible mechanism for stereoselective epoxidation of 3 with oxone is as
follows..
14. Bloch, R.; Abecassis, J.; Hassan, D. J. Org. Chem. 1985, 50, 1544–
1545.
15. Trost, B. M.; Calkins, T. L.; Bochet, C. G. Angew. Chem., Int. Ed. 1997, 36, 2632–
2635.
(3): ½a 2D0
ꢀ
ꢁ42.3 (c 0.625, CHCl3); FT-IR (thin film, neat) vmax 3295, 2919,
1739, 1653, 1552, 1481, 1438, 1365 cmꢁ1
;
1H NMR (CDCl3, 400 MHz, mixture
of rotamers) d 7.37 (m, 1H), 7.23 (m, 2H), 7.15 (m, 2H), 6.62 (m, 1H), 5.61–5.35
(m, 2H), 4.05 (m, 1H), 3.59 (m, 1H), 3.34 (m), 3.06 (m), 2.88–2.75 (m, 2H), 2.64
(m), 2.54 (d, 1H, J = 13.0 Hz), 2.23 (m, 1H), 1.89 (m, 2H), 1.50 (m, 1H), 1.26 (m,
2H); 13C NMR (CDCl3, 100 MHz) d 169.9, 137.1, 134.6, 129.2, 129.2, 128.2,
128.2, 126.5, 124.6, 54.6, 40.5, 36.5, 32.7, 29.5, 28.9; LR-MS (FAB+) m/z 262
(M+H+); HR-MS (FAB+) calcd for C15H20NOS (M+H+) 262.1266; found 262.1271.
(1R,3S,9aS)-1-hydroxy-3-(phenylsulfonyl)hexahydro-1H-quinolizin-4(6H)-one