Total synthesis of (+)-azimine via diastereoselective aminopalladation

Article abstract of DOI:10.1016/j.tet.2013.07.083

The aminopalladation of amino allylic alcohol using Cl₂Pd(MeCN) ₂ in CH₂Cl₂ gave the 2,6-disubstituted piperidine with excellent diastereoselectivity. This compound was successfully converted into (+)-azimine (1

Full text of DOI:10.1016/j.tet.2013.07.083

Tetrahedron 69 (2013) 8349e8352
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (þ)-azimine via diastereoselective
aminopalladation
Yuji Kurogome a, Masaya Kogiso a, Kok Kong Looi b, Yasunao Hattori c, Hiroyuki Konno d,
,
Mitsuru Hirota b, Hidefumi Makabe a
*
a Graduate School of Agriculture, Sciences of Functional Foods, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan
b Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan
c Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
d Department of Biochemical Engineering, Graduate School of Science and Technology, Yamagata University, Yonezawa, Yamagata 992-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 June 2013
Received in revised form 22 July 2013
Accepted 25 July 2013
Available online 4 August 2013
The aminopalladation of amino allylic alcohol using Cl2Pd(MeCN)2 in CH2Cl2 gave the 2,6-disubstituted
piperidine with excellent diastereoselectivity. This compound was successfully converted into (þ)-azi-
mine (1) using cross-metathesis and Shiina macrolactonization.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Piperidine
Natural product
Aminopalladation
1. Introduction
Among a lot of numbers of biologically active natural com-
pounds, the alkaloids are most paid attention due to their signifi-
cant biological activities and unique structures.1,2 Most of
piperidine alkaloids possess a chiral center at C2 and/or C6 position,
thus stereoselective construction is very important. For example,
excellent diastereoselective syntheses have been achieved as fol-
lows. Stereoselective synthesis of trans-2,6-disubstituted piperi-
dine alkaloids using Pd(0) catalyzed N-alkylation has been achieved
by Tadano in 1993.3 In 2000, Hirai reported Pd(II) catalyzed cycli-
zation of amino allylic alcohol to afford 2-substituted piperidine
with excellent diastereoselectivity.4
Fig. 1. The structures of (þ)-azimine (1) and (þ)-azimic acid (2).
While most of alkaloids generally exist as monomers, (þ)-azi-
mine (1) is macrocyclic dilactone, which was isolated from Azima
tetracantha L.5,6 Structurally, azimine (1) is a dimer of (þ)-azimic
acid (2), which has 2-methyl-3-piperidinol skeleton with a carboxyl
group at terminal position. This compound is presumed bio-
synthetic and synthetic precursor of (þ)-azimine (1) (Fig. 1). The
syntheses of (þ)-azimic acid (2) were reported by many re-
searchers,7 however, there is only one example of asymmetric total
synthesis of (þ)-azimine (1) by Kibayashi and co-workers using
stereoselective intramolecular hetero-DielseAlder reaction of an
acylnitroso compound.8
In our previous report, we accomplished an asymmetric total
synthesis of (ꢀ)-cassine using diastereoselective aminopalladation,
however, the yield of this reaction was not high enough.9 Therefore,
we have investigated to improve the yield and found that the effect
of solvent was useful for diastereoselective aminopalladation. Here
we wish to report improved diastereoselective Pd(II)-catalyzed
cyclization and its application to the total synthesis of azimine (1).
* Corresponding author. Tel.: þ81 265 77 1630; fax: þ81 265 77 1700; e-mail
address: makabeh@shinshu-u.ac.jp (H. Makabe).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.083

8350
Y. Kurogome et al. / Tetrahedron 69 (2013) 8349e8352
2. Results and discussion
give 4a in a moderate yield.9 Using Pd(II) catalysts with phosphine
ligands such as PPh3 and dppf did not afford cyclized product. We
also examined allylic ester such as pivaloyl, mesityl, and biphenyl
esters because Hirai reported Pd(II) catalyzed cyclization of amino
allylic pivaloyl ester afforded 3,4,5,6-substituted piperidine with
excellent diastereoselectivity in 36% yield.4 However, the yield of
cyclized product was very low in our cases. We found that using
allylic ester was difficult to construct 2,6-piperidine ring. Finally,
Scheme 1 outlines our synthetic strategy. (þ)-Azimine (1) would
be derived from 3 via macrolactonization. Hydroxy carboxylic acid
3 would be prepared via several steps from 4a and methyl 5-
hexenate including Grubbs cross-metathesis. Piperidine 4a would
be synthesized using similar procedure from 5 as we reported
previously (Scheme 1).9
Scheme 1. Synthetic strategy of (þ)-azimine (1).
The cyclization precursor 5 was synthesized from 1,5-hexadiyne
as we reported earlier.9 The results of diastereoselective amino-
palladation of 5 and its derivatives are summarized in Table 1. At
first we used the reaction condition as we have reported before to
we switched the solvent from THF to CH2Cl2 to afford 4a in good
yield.
Because we have optimized the reaction condition for stereo-
selective aminopalladation to prepare 4a, we began total synthesis
Table 1
Stereoselective aminopalladation of 5 and its derivatives
Entry
R
Catalyst
Solvent
Time (h)
Yield % (4a/4b)
4a/4ba
1
2
3
4
H
H
H
H
PdCl2
THF
THF
THF
THF
12
12
24
24
61
39
0
>49:1
>49:1
d
Cl2Pd(MeCN)2
Cl2Pd(PPh3)2
Cl2Pd(dppf)
0
d
5
6
7
Cl2Pd(MeCN)2
THF
24
Trace
d
Cl2Pd(MeCN)2
THF
24
0
d
Cl2Pd(MeCN)2
Cl2Pd(MeCN)2
THF
24
20
0
d
8
H
CH2Cl2
82
>49:1
a
The relative stereochemistry of 4a was determined by 2D-NOESY experiment.9

Y. Kurogome et al. / Tetrahedron 69 (2013) 8349e8352
8351
of (þ)-azimine (1). Cross-metathesis between 4a and methyl 5-
hexenate using second-generation HoveydaeGrubbs catalyst
afforded chain elongated compound 6 in 88% yield.10 Using second
generation of Grubbs catalyst gave 6 only in 14% yield. Compound 6
was subjected to catalytic hydrogenation using 5% Pearlman’s cat-
alyst to give saturated product 7. Deprotection of the MOM and the
Boc groups with HCl in MeOH subsequent treatment with CbzCl and
NaHCO3 afforded 8.11 Treatment of 8 with Ba(OH)2$8H2O afforded
hydroxy carboxylic acid 9 whose 1H NMR, 13C NMR data were in
good agreement with those of the reported values by Kibayashi and
co-workers.8 Macrocyclic dilactonization of 9 was attempted using
Yamaguchi macrolactonization as reported Kibayashi and co-
workers.8 Although Kibayashi et al. reported this reaction was pro-
ceeded in 71% yield, actually the yield from 9 to 10 was only 34% in
our experiment. Thus we switched to use Shiina macrolactonization
to generate 10 in 68% yield.12 Yamaguchi’s method was generally
carried out using largeexcess amount of base.13 Longerreaction time
might cause decomposition of macrolactone 9. On the other hand,
Shiina’s protocol did not need to use excess amount of base. Finally,
spectrometer in CDCl3 at 500 and 125 MHz, respectively.
Chemical shifts were relative to tetramethylsilane as an internal
standard. The coupling constants were given in hertz (Hz). Mass
spectra were obtained on JEOL JMS-700, JEOL JMS-SX102A,
and TMS-T100 LC mass spectrometer. IR spectra were
recorded with JASCO FT-IR 480 Plus infrared spectrometer. Op-
tical rotations were determined with
polarimeter.
a JASCO DIP-1000
4.2. (2S,3S,6S)-2-Methyl-N-tert-butoxycarbonyl-3-
methoxymethoxy-6-vinylpiperidine (4a)
To a solution of 5 (116 mg, 0.38 mmol) in CH2Cl2 (5 mL) was
added Cl2Pd(CH3CN)2 (5 mg, 19 m
mol) at 0 ꢁC and the mixture was
stirred for 12 h at room temperature. The reaction mixture was
diluted with water and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and concentrated. The res-
idue was purified by preparative TLC (hexane/AcOEt¼5:1, Rf¼0.36)
to give 4a (89 mg, 82%) as a colorless oil. [
a
]
19 ꢀ47 (c 1.1, CHCl3). IR
D
hydrogenolysis of the Cbz group furnished (þ)-azimine (1). The
(film) nmax cmꢀ1: 3080, 2980, 2930, 2880, 1690, 1450, 1395, 1370,
20
optical rotation of synthetic 1 was consistent with {[
a
]
þ3.10 (c
1240, 1170, 1100, 1040, 965, 920. 1H NMR
d
: 1.12 (3H, d, J¼7.0 Hz),
D
0.30, EtOH)} that reported by Kibayashi and co-workers {[
a
]
25 þ3.14
D
1.47 (9H, s), 1.60e1.75 (3H, m), 1.96 (1H, m), 3.37 (3H, s), 3.66 (1H,
m), 4.46 (1H, qd, J¼6.6, 6.6 Hz), 4.63 (1H, br s), 4.67 (2H, s), 5.08 (1H,
d, J¼10.6 Hz), 5.13 (1H, d, J¼17.4 Hz), 5.91 (1H, ddd, J¼17.0, 10.5,
(c 0.74, EtOH)}.8 The 1H NMR, 13C NMR, and MS spectra and melting
point of synthetic 1 were also in good agreement with those of the
reported values (Scheme 2).8
5.3 Hz). 13C NMR
d: 14.1, 21.0, 26.3, 28.4, 49.5, 50.7, 55.4, 74.7, 79.7,
Scheme 2. Synthesis of (þ)-azimine (1). Regents and conditions: (a) HoveydaeGrubbs second catalyst, CH2Cl2, reflux, 88%; (b) H2, 5% Pd(OH)2/C, 99%; (c) (i) HCl, MeOH, (ii) CbzCl,
NaHCO3, dioxane/H2O, 73%; (d) Ba(OH)2$8H2O, MeOH, 40 ꢁC, 85%; (e) Shiina macrolactonization, 68%; (f) H2, 5% Pd(OH)2/C, quant.
3. Conclusion
95.0, 114.6, 140.0, 155.1. HREIMS [M]þ: found, 285.1947, calcd for
15H27NO4: 285.1940.
C
In conclusion, we have achieved a total synthesis of (þ)-azimine
(1) using a diastereoselective aminopalladation. The key in-
termediate 4a can be used as building blocks for synthesizing other
cis-2,6-disubstituted piperidine alkaloids.
4.3. Methyl 6-{(2S,3S,5EZ,6S)-1-[(tert-butoxy)carbonyl]-5-
methoxymethoxy-6-methylpiperidine-2-yl}-hex-5-enoate (6)
To a solution of 4a (29 mg, 0.10 mmol) and methyl hex-5-enoate
(33 mg, 0.26 mmol) in CH2Cl2 (5.0 mL) was added HoveydaeGrubbs
second catalyst (6.4 mg, 0.010 mmol). After being stirred for 3 h
under reflux, additional solution of HoveydaeGrubbs second cat-
alyst in CH2Cl2 (6.4 mg, 0.010 mmol) and methyl 5-hexenoate
(33 mg, 0.26 mmol) was added. After being stirred for 3 h under
reflux, the solvent was removed and the residue was purified by
4. Experimental
4.1. General
All melting points were uncorrected. 1H and 13C NMR
spectra were measured with
a Bruker DRX 500 FT-NMR

8352
Y. Kurogome et al. / Tetrahedron 69 (2013) 8349e8352
preparative TLC (hexane/AcOEt¼10:1, Rf¼0.24) to give 6 (35 mg,
4.7. Dibenzyl (1S,9R,11S,12S,20R,22S)-11,22-dimethyl-3,14-
dioxa-2,13-dioxo-10,21-diazatricyclo[18.2.2.29,12]hexacosane-
10,21-dicarboxylate (10)
20
88%, E/Z¼9:1) as a colorless oil. [
nmax cmꢀ1: 2945, 2848, 1739, 1688, 1366, 1246, 1173, 1043, 965. 1H
NMR (E isomer)
a
]
ꢀ21 (c 0.25, CHCl3). IR (film)
D
d
: 1.12 (3H, d, J¼7.0 Hz), 1.46 (9H, s), 1.62e1.87 (6H,
m), 2.05 (2H, m), 2.32 (2H, t, J¼7.5 Hz), 3.38 (3H, s), 3.64 (1H, m),
To a solution of 2-methyl-6-nitrobenzoic anhydride (43 mg,
0.13 mmol) and DMAP (49 mg, 0.4 mmol) in CH2Cl2 (21 mL) was
added a solution of 9 (37 mg, 0.10 mmol) in THF (34 mL) over 6 h.
After being stirred for 1 h, the reactionwas quenched with saturated
aqueous NaHCO3 at 0 ꢁC and the mixture was extracted with diethyl
ether, washed with water, brine, and dried over Na2SO4. Concen-
tration and purification by preparative TLC (hexane/EtOAc/
ether¼2:2:1, Rf¼0.16) afforded 10 (24 mg, 68%) as a colorless oil.
3.66 (3H, s), 4.44 (1H, m), 4.60 (1H, brs), 4.67 (2H, s), 5.53 (2H, m).
13C NMR (E isomer)
d: 14.4, 21.1, 24.4, 27.1, 28.5, 31.8, 33.3, 49.3, 51.4,
55.4, 74.7, 79.6, 95.0, 129.7, 132.5, 155.1, 174.0. HRFABMS [MþH]þ:
found, 386.2549, calcd for C20H36NO6: 386.2543.
4.4. Methyl 6-{(2S,3S,6R)-1-[(tert-butoxy)carbonyl]-5-
methoxymethoxy-6-methylpiperidine-2-yl}-hexanoate (7)
[a
]
20 ꢀ14 (c 0.40, CHCl3). IR (film) nmax cmꢀ1: 2942, 2860,1733,1694,
D
The mixture of 6 (49 mg, 0.13 mmol) and Pd(OH)2/C (5% w/w,
2.5 mg) in MeOH (4.0 mL) was stirred under hydrogen atmosphere.
After being stirred for 5 h, the reaction mixture was filtered and
concentrated. The residue was purified by preparative TLC (hexane/
1497,1455,1411,1381,1298,1236,1150,1120,1087,1022, 753, 698.1H
NMR (CDCl3, 1.35:1 amide rotamers)
d
: 1.21 (2.6H, d, J¼7.0 Hz), 1.25
(3.4H, d, J¼7.0 Hz), 1.20e1.85 (24H, m), 2.21e2.43 (4H, m), 4.15
(0.85H, br s), 4.20 (1.15H, br s), 4.56 (0.85H, q, J¼7.0 Hz), 4.64 (1.15H,
q, J¼7.0 Hz), 4.84e4.92 (2H, m), 5.13 (4H, br s), 7.29e7.38 (10H, m).
AcOEt¼10:1, Rf¼0.25) to afford 7 (49 mg, 99%) as a colorless oil.
20
[
a]
ꢀ12.8 (c 0.18, CHCl3). IR (film) nmax cmꢀ1: 2944, 2861, 1740,
13C NMR
d: 16.1, 16.20, 20.1, 20.2, 24.4, 24.5, 25.3, 25.6, 25.8, 26.0,
D
1686, 1439, 1405, 1366, 1321, 1174, 1146, 1043, 918. 1H NMR
d: 1.13
28.5, 28.7, 29.7, 33.7, 33.9, 34.4, 34.7, 47.9, 48.0, 49.8, 49.9, 67.2, 67.3,
70.7, 70.8, 128.0, 128.5, 136.7, 155.7, 172.1, 172.2. HRFABMS [MþH]þ:
found, 691.3955, calcd for C40H55N2O8: 691.3958.
(3H, d, J¼7.0 Hz), 1.25e1.31 (12H, m), 1.46 (9H, s), 2.32 (2H, m), 3.38
(3H, s), 3.63 (1H, m), 3.67 (3H, s), 3.99 (1H, br s), 4.43 (1H, br s), 4.67
(2H, s). 13C NMR
d: 14.3, 20.7, 24.9, 26.4, 27.5, 28.5, 29.1, 34.0, 34.8,
49.7, 51.4, 55.4, 74.9, 79.4, 94.9, 155.2, 174.1. HRFABMS [MþH]þ:
4.8. (D)-Azimine (1)
found, 388.2693, calcd for C20H38NO6: 388.2699.
The mixture of 10 (7.0 mg, 0.01 mmol) and Pd(OH)2/C (5% w/w,
0.4 mg) in MeOH (0.4 mL) was stirred under hydrogen atmosphere.
After being stirred for 20 h, the reaction mixture was filtered and
concentrated to afford 1 (6.2 mg, quant.) as a colorless solid. Mp
4.5. Methyl 6-{(2S,3S,6R)-1-[(benzyloxy)carbonyl]-5-hydroxy-
6-methylpiperidine-2-yl}-hexanoate (8)
111e112 ꢁC. [
a]
D
20 þ3.10 (c 0.30, EtOH). IR (film) nmax cmꢀ1: 3390, 2930,
To a solution of 7 (47 mg, 0.12 mmol) in MeOH (2.0 mL) was
added a few drops of concd HCl. After being stirred for 19 h, the
mixture was extracted with CHCl3, washed with 10% aqueous NH3,
brine, and dried over K2CO3. Concentration afforded crude hy-
droxylamine, which was used for the next step without further
purification. To a solution of hydroxylamine in 1,4-dioxane (1.0 mL)
and H2O (1.0 mL) was added CbzCl (0.18 mL,1.23 mmol). After being
stirred for 72 h, the reaction was quenched with water and the
mixture was extracted with EtOAc, washed with saturated aqueous
NaHCO3, brine, and dried over MgSO4. Concentration and purifi-
cation by preparative TLC (hexane/AcOEt¼2:1, Rf¼0.22) afforded 8
2856, 1728, 1252, 1157, 1114, 1075, 973. 1H NMR (CDCl3)
d: 1.05 (6H, d,
J¼6.5 Hz), 1.10e1.80 (24H, m), 2.03 (2H, dq, J¼14.0, 3.0 Hz), 2.28e2.50
(4H, m), 2.57e2.70 (2H, m), 2.87 (2H, q, J¼6.5 Hz), 4.78 (2H, s).13C NMR
d
: 18.9, 25.0, 25.4, 26.3, 29.1, 29.4, 34.9, 37.3, 53.6, 55.6, 70.4, 172.9.
HRFABMS [MþH]þ: found, 423.3213, calcd for C24H43N2O4: 423.3224.
Acknowledgements
This work was supported in part by a Grant-in-aid from the
Japan Society for the Promotion of Science (24580160) to H.M.
(46 mg, 73%, two steps) as a colorless oil. [
a
]
19 ꢀ4.7 (c 0.46, CHCl3).
D
IR (film) nmax cmꢀ1: 3448, 2942, 2861, 1737, 1692, 1497, 1412, 1299,
Supplementary data
1172, 1071, 1029, 737, 699, 669. 1H NMR (CDCl3)
d: 1.13 (3H, d,
J¼7.0 Hz), 1.22e1.75 (13H, m), 2.27 (2H, t, J¼7.5 Hz), 3.67 (3H, s),
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.07.083.
3.76 (1H, m), 4.10 (1H, br s), 4.50 (1H, m), 5.16 (2H, m), 7.29e7.40
(5H, m). 13C NMR
d: 13.7, 23.0, 24.8, 26.4, 26.9, 29.0, 34.0, 34.7, 49.9,
50.8, 51.4, 67.1, 69.8, 127.9, 128.5, 136.9, 155.9, 174.1. HRFABMS
References and notes
[MþH]þ: found, 378.2284, calcd for C21H32NO5: 378.2280.
1. Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic: New York,
NY, 1985; Vol. 26, p 89.
2. Koulocheri, S. D.; Pitsinos, E. N.; Haroutounian, S. A. Curr. Org. Chem. 2008, 12,
1454.
4.6. 6-{(2R,5S,6S)-1-[(Benzyloxy)carbonyl]-5-hydroxy-6-
methylpiperidine-2-yl}hexanoic acid (9)
3. (a) Tadano, K.; Takao, K.; Nigawara, Y.; Nishio, E.; Takagi, I.; Maeda, K.; Ogawa, S.
Synlett 1993, 565; (b) Takao, K.; Nigawara, E.; Nishio, E.; Takagi, I.; Maeda, K.;
Tadano, K.; Ogawa, S. Tetrahedron 1994, 50, 5681.
4. Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y.
Org. Lett. 2000, 2, 2427.
5. Rall, G. J. H.; Smalberger, T. M.; de Waal, H. L. Tetrahedron Lett. 1967, 8, 3465.
6. Smalberger, T. M.; Rall, G. J. H.; de Waal, H. L.; Arndt, R. R. Tetrahedron 1968, 24,
6417.
7. Recent examples of synthesis of (þ)-azimic acid (2): (a) Bates, R. W.; Kasina-
than, S. Tetrahedron 2013, 69, 3088; (b) Xiao, K.-J.; Liu, L.-X.; Huang, P.-Q. Tet-
rahedon: Asymmetry 2009, 20, 1181; (c) Leverett, C. A.; Cassidy, M. P.; Padwa, A.
J. Org. Chem. 2006, 71, 8591; (d) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029.
8. Sato, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3839.
9. Makabe, H.; Looi, K. K.; Hirota, M. Org. Lett. 2003, 5, 27.
10. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
11. Masuda, Y.; Tashiro, T.; Mori, K. Tetrahedron: Asymmetry 2006, 17, 3380.
12. Shiina, I. Chem. Rev. 2007, 107, 239.
To a solution of 8 (46 mg, 0.12 mmol) in MeOH (2.8 mL) was
added Ba(OH)2$8H2O (194 mg, 0.60 mmol). After being stirred for
48 h at 40 ꢁC, the reaction was quenched with 1 N HCl and the
mixture was extracted with diethyl ether, washed with water,
brine, and dried over MgSO4. The residue was purified by pre-
parative TLC (CHCl3/MeOH¼5:1, Rf¼0.21) to afford 9 (37 mg, 85%) as
a colorless oil. [
a]
20 ꢀ8.42 (c 1.04, CHCl3). IR (film) nmax cmꢀ1: 3419,
D
2939, 2860, 1669, 1540, 1497, 1417, 1300, 1145, 1096, 1069, 1027, 770,
736, 698, 668. 1H NMR (CDCl3)
d
: 1.15 (3H, d, J¼7.0 Hz), 1.22e1.75
(12H, m), 2.24 (2H, t, J¼7.5 Hz), 3.74 (1H, m), 4.11 (1H, br s), 4.48
(1H, m), 5.14 (2H, m), 6.10e6.70 (2H, br), 7.29e7.41 (5H, m). 13C
NMR d: 13.7, 22.9, 24.8, 26.4, 26.8, 26.9, 29.0, 34.3, 34.5, 49.9, 50.9,
67.2, 69.7, 127.8, 128.0, 128.5, 136.7, 156.0, 179.3. HRFABMS [MþH]þ:
13. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.
found, 364.2128, calcd for C20H30NO5: 364.2124.