Enantioselective synthesis of the diazatricyclic core of alkaloid TAN1251C via an iodoaminocyclization reaction

Article abstract of DOI:10.1002/cjoc.201090290

A concise enantioselective synthesis of the diazatricyclic core of alkaloid TAN1251C is reported. The method featured a stereoselective formation of the iodide intermediate 16b (in 2:1 ratio) from homoallylic amine 11b by iodine-promoted iodoaminocyclizat

Full text of DOI:10.1002/cjoc.201090290

FULL PAPER
Enantioselective Synthesis of the Diazatricyclic Core of
Alkaloid TAN1251C via an Iodoaminocyclization Reaction†
Zhang, Hongkui*(张洪奎)
Lin, Zhijie(林智杰)
Huang, Huang(黄璜)
Huo, Haohua(霍浩华)
Huang, Yanju(黄燕菊)
Ye, Jianliang(叶剑良)
Huang, Peiqiang*(黄培强)
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
A concise enantioselective synthesis of the diazatricyclic core of alkaloid TAN1251C is reported. The method
featured a stereoselective formation of the iodide intermediate 16b (in 2∶ 1 ratio) from homoallylic amine 11b by
iodine-promoted iodoaminocyclization, a previously claimed to be unsuccessful reaction. The intermediate 16b was
converted to the tricyclic core of TAN1251C 28 in five steps. During this study, two unexpected products 22 and 25
were obtained, and compound 23, derived from 11a was shown to be unsuitable for the oxidative formation of the
enamide of TAN1251C.
Keywords alkaloids, iodoaminocyclization, azaspirane, asymmetric synthesis
Introduction
The attractive biological activity of TAN1251 com-
pounds and unique diazatricyclic structure have at-
tracted significant attention from synthetic organic
chemists, and several approaches for the synthesis of
TAN1251 alkaloid have been published.5-8 Most of them
have been devoted to the synthesis of TAN1251A.5
Comparatively, little attention was focused on the
asymmetric synthesis of TAN1251C.7 Most synthetic
approaches to TAN1251 alkaloid involved initial forma-
tion of a 1-azaspiro[4,5]decane,9 followed by a
ring-closure reaction to form the tricyclic system.10
Kawahara and co-workers5b,5c,5g used compound 5a and
5b to synthesize (－) and (＋)-TAN1251A. Similarly,
Wardrop’s group synthesized (－)-TAN1251A using
azaspiro compound 6.5e Recently, Snider and Ciufolini
reported the synthesis of TAN1251C via building block
75f and 87b, respectively (Figure 2).
The TAN1251 series of alkaloids including
TAN1251A (1), TAN11251B (2), TAN1251C (3), and
TAN1251D (4) were isolated from a Penicillium thomii
RA89 fermentation broth at Takeda Industries1 (Figure
1). TAN1251A and TAN1251B exhibit cholinergic ac-
tivity and cause acetylcholine-induced contraction of
Guinea-pig ileum.2 TAN1251A is also known as a selec-
tive muscarinic M1 subtype receptor antagonist.3 The
affinity of TAN1251B to a muscarinic acetylcholine
receptor is stronger than that of atropine. Like its con-
geners, TAN1251C is a muscarinic antagonist of poten-
tial interest in the treatment of ulcer.4
With the aim to develop an asymmetric approach to
TAN1251C, optically active 1-azaspiro[4,5]decane de-
rivative 9a was selected as a common intermediate in
our initial study (Scheme 1). Compound 9a could be
prepared from iodide 16a. The later was envisioned to
be synthesized from optically active homoallylic amine
11a by iodine-promoted iodoaminocyclization reac-
tion.11
Experimental
Optical rotations were recorded on a Perkin-Elmer
Figure 1 The structures of TAN1251 family.
1
341 automatic polarimeter. H NMR and 13C NMR
*
E-mail: pqhuang@xmu.edu.cn; hkzhang@xmu.edu.cn
Receiced July 22, 2010; revised and accepted August 13, 2010.
Project supported by the National Natural Science Foundation of China (No. 20672089).
† Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
Chin. J. Chem. 2010, 28, 1717— 1724
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zhang et al.
FULL PAPER
chromatography, eluting (unless otherwise stated) with
ethyl acetate (EtOAc)/petroleum ether (PE) (60—90 ℃)
mixture.
Compounds 12a and 12b were prepared essentially
according to the literature procedure,11b excepted that all
the reactions were preformed at 0 ℃ or at room tem-
perature.
(8-Allyl-1,4-dioxa-spiro[4.5]dec-8-yl)-[1-(4-benzyloxy-
benzyl)-2-(tert-butyldimethylsilanyloxy)-ethyl]-
amine (11a)
To a solution of 1,4-cyclohexanedione monoethylene
acetal (126 mg, 0.8 mmol) in CH2Cl2 (2 mL) was added
4 Å molecular sieves (0.5 g) and a solution of com-
pound 12a (300 mg, 0.8 mmol) in CH2Cl2 (2 mL). After
stirring at room temperature overnight, the suspension
was filtered through a celite, and the filtrate was con-
centrated under reduced pressure to give the corre-
sponding imine 13a. To a solution of this imine in Et2O
(4 mL) was added dropwise allylmagnesium bromide
(4.0 mL, 0.5 mol/L). The reaction was stirred at 0 ℃
for 2 h, then at r.t. for 2 h and the reaction was quenched
with NH4Cl (4 mL), H2O (2 mL), and extracted with
CH2Cl2 (4 mL×3). The organic extracts were washed
with brine, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified
by flash column chromatography on silica gel eluting
with [V(PE)∶V(EtOAc)＝10∶1] to give amine 11a
(279 mg, 82%) as a colorless oil. [α] 2D0 －3.0 (c 1.3,
Figure 2 The structures of some azaspirane compounds.
Scheme 1 Retrosynthetic analysis of TAN1251C (3)
1
MeOH); H NMR (CDCl3, 400 MHz) δ: 0.03 (s, 6H),
0.90 (s, 9H), 1.40—1.80 (m, 8H), 2.10—2.20 (m, 2H),
2.65 (dd, J＝5.8, 13.5 Hz, 1H), 2.77 (dd, J＝7.2, 13.5
Hz, 1H), 2.85—2.92 (m, 1H), 3.32 (dd, J＝6.0, 9.8 Hz,
1H), 3.45 (dd, J＝4.4, 9.8 Hz, 1H), 3.91 (s, 4H), 4.98—
5.05 (m, 4H), 5.70—5.85 (m, 1H), 6.88 (d, J＝8.6 Hz,
2H), 7.10 (d, J＝8.6 Hz, 2H), 7.30—7.44 (m, 5H); 13C
NMR (CDCl3, 100 MHz) δ: －5.4, －5.3, 18.3, 26.0,
30.6, 30.7, 33.2, 39.6, 53.6, 53.8, 64.1, 65.7, 70.1, 108.9,
114.7, 117.3, 127.4, 127.8, 128.5, 130.5, 132.1, 134.8,
137.3, 157.2; IR (film) ν: 3067, 3030, 2928, 2856, 1610,
－1
1510, 1470, 1247, 1103 cm ; MS (ESI) m/z: 552 (M＋
H＋). Anal. calcd for C33H49NO4Si: C 71.82, H 8.95, N
2.54; found C 71.48, H 8.77, N 2.43.
spectra were recorded on a Bruker 400 spectrometer. 1H
NMR spectra were registered in CDCl3, and chemical
shifts are expressed relative to internal Me4Si. IR spec-
tra were recorded on a Nicolet Avatar 360 RT-IR spec-
trophotometer. Mass spectra were recorded by Bruker
Dalton Esquire 3000 plus and Finnigan Mat-LCQ (ESI
direct injection). HRFABMS spectra were recorded on a
Bruker APEX-FTMS apparatus. Elemental analyses
were performed using a Vario RL analyzer. Melting
points were determined on a Yanaco MP-500 melting
point apparatus and are uncorrected.
Tetrahydrofuran (THF) was distilled prior to use
from sodium benzophenone ketyl. Dichloromethane was
distilled from phosphorus pentoxide. Dimethylforma-
mide was distilled from calcium hydride. Silica gel from
Yantai silica gel factory (China) was used for column
2-[11-(Benzylmethylamino)-1,4-dioxa-9-azadispiro-
[4.2.4.2]tetradec-9-yl]-3-(4-benzyloxyphenyl)-propan-
1-ol (18a) and 2-[11-(benzylmethylamino)-1,4-dioxa-
9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-benzyloxy-
phenyl)-propan-1-ol (19a)
A solution of iodine (50 mg, 0.09 mmol) in CH2Cl2
(1 mL) was added dropwise to a mixture of amine 11a
(50 mg, 0.09 mmol) in CH2Cl2 (0.36 mL) and 5%
aqueous NaHCO3 (1 mL). After stirring for 4 h at room
temperature, a 10% aqueous Na2S2O3 (5 mL) was added.
The mixture was extracted with CH2Cl2 (5 mL×4). The
combined organic phases were concentrated under re-
duced pressure to give a diastereomeric mixture of io-
dides 16a, which was used in the next step without fur-
ther purification.
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1717— 1724

Enantioselective Synthesis of the Diazatricyclic Core of Alkaloid TAN1251C
(8-Allyl-1,4-dioxaspiro[4.5]dec-8-yl)-[2-(tert-butyldi-
methylsilanyloxy)-1-(4-methoxybenzyl)-ethyl]-amine
(11b)
To a solution of the diastereomeric mixture of io-
dides 16a (0.09 mmol) in CH3CN (0.2 mL) were added
benzylmethylamine (32 mg, 0.27 mmol) and K2CO3 (37
mg, 0.27 mmol). After stirring at 40 ℃ overnight, the
suspension was filtered through Celite and the filtrate
was concentrated under reduced pressure. The residue
was purified by chromatography on silica gel [V(PE)∶
V(EtOAc)＝10∶1] to afford diamine 17a (26 mg, 44%
from 11a) as a diastereomeric mixture. 17a was used in
the next step without further purification.
To a solution of 1,4-cyclohexanedione monoethylene
acetal (126 mg, 0.8 mmol) in CH2Cl2 (2 mL) were
added 4 Å molecular sieves (0.5 g) and a solution of
compound 12b (240 mg, 0.8 mmol) in CH2Cl2 (2 mL).
After stirring at room temperature overnight, the sus-
pension was filtered through Celite, and the filtrate was
concentrated under reduced pressure to give the corre-
sponding imine 13b. To a solution of this imine in Et2O
(4 mL) was added dropwise allylmagnesium bromide
(4.0 mL, 0.5 mol/L). The reaction was stirred at 0 ℃
for 2 h, then at r.t. for 2 h and the reaction was quenched
with NH4Cl (4 mL), H2O (2 mL), and extracted with
CH2Cl2 (4 mL×3). The organic extracts were washed
with brine, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel
eluting with [V(PE)∶V(EtOAc)＝10∶1] to give amine
11b (310 mg, 82%) as a colorless oil. [α] 2D0 －2.8 (c
To a solution of the diastereomeric mixture of 17a
(20 mg, 0.03 mmol) in THF (0.06 mL) was added a so-
lution of tetrabutylammonium fluoride (TBAF) (1
mol/L in THF, 0.1 mL). After stirring for 12 h at room
temperature, the reaction was quenched with water and
extracted with EtOAc (3 mL×3). The combined ex-
tracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chroma-
tography on silica gel eluting with [V(PE)∶V(EtOAc)
＝1∶1] to afford alcohols 18a (10 mg, 60%) as a col-
orless oil and 19a (5 mg, 30%) as a colorless oil. 18a:
1
0.9, MeOH); H NMR (CDCl3, 400 MHz) δ: 0.03 (s,
6H), 0.91 (s, 9H), 1.40—1.60 (m, 6H), 1.60—1.81 (m,
2H), 2.09—2.21 (m, 2H), 2.65 (dd, J＝5.8, 13.5 Hz,
1H), 2.75 (dd, J＝7.2, 13.5 Hz, 1H), 2.87—2.95 (m,
1H), 3.31 (dd, J＝6.0, 9.8 Hz, 1H), 3.45 (dd, J＝4.4, 9.8
Hz, 1H), 3.79 (s, 3H), 3.91 (s, 4H), 4.98—5.05 (m, 2H),
5.70—5.82 (m, 1H), 6.80 (d, J＝8.6 Hz, 2H), 7.10 (d,
J＝8.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: －5.3,
－5.4, 18.3, 25.9, 30.6, 30.7, 33.2, 39.5, 42.8, 53.6, 53.8,
55.3, 64.1, 65.6, 108.9, 113.7, 117.2, 130.5, 131.8, 134.8,
158.0; IR (film) ν: 2952, 2929, 2857, 1611, 1512, 1247,
1
[α] 2D0 －40.3 (c 0.5, MeOH); H NMR (CDCl3, 400
MHz) δ: 1.24—1.33 (m, 2H), 1.65—1.84 (m, 6H), 1.85
—1.98 (m, 2H), 2.12 (s, 3H), 2.22 (dd, J＝7.4, 12.7 Hz,
1H), 2.45 (dd, J＝10.2, 13.2 Hz, 1H), 2.80—2.91 (m,
2H), 2.98 (dd, J＝1.0, 12.1 Hz, 1H), 3.10—3.20 (m,
3H), 3.29 (dd, J＝10.9, 16.0 Hz, 1H), 3.45 (d, J＝12.9
Hz, 1H), 3.56 (d, J＝12.9 Hz, 1H), 3.92—3.97 (m, 4H),
5.03 (s, 2H), 6.89 (d, J＝8.6 Hz, 2H), 7.07 (d, J＝8.6
Hz, 2H), 7.24—7.43 (m, 10H); 13C NMR (CDCl3, 100
MHz) δ: 31.8, 32.1, 33.0, 35.6, 36.3, 40.3, 40.8, 48.0,
56.0, 60.3, 60.8, 62.4, 62.5, 64.2, 64.3, 70.0, 108.0,
115.0, 127.0, 127.4, 127.8, 128.2, 128.5, 129.1, 129.7,
131.1, 137.0, 138.5, 157.2; IR (film) ν: 3404, 2946,
＋
－1
1108 cm ; MS (ESI) m/z: 476 (M＋H ). Anal. calcd
for C27H45NO4Si: C 68.17, H 9.53, N 2.94; found C
68.47, H 9.84, N 3.09.
2-[11-(Benzylmethylamino)-1,4-dioxa-9-azadispiro-
[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)-propan-
1-ol (18b) and 2-[11-(benzylmethylamino)-1,4-dioxa-
9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphen-
yl)-propan-1-ol (19b)
－1
2857, 1510, 1453, 1369, 1240, 1106, 1028 cm ; MS
(ESI) m/z: 557 (M＋H＋). Anal. calcd for C35H44N2O4: C
75.51, H 7.97, N 5.03; found C 75.13, H 7.55, N 4.96.
1
19a: [α] 2D0 －8.2 (c 1.3, MeOH); H NMR (CDCl3,
400 MHz) δ: 1.30—1.40 (m, 1H), 1.52—1.82 (m, 7H),
2.02 (td, J＝4.0, 13.5 Hz, 1H), 2.15 (s, 3H), 2.31 (dd,
J＝7.4, 12.5 Hz, 1H), 2.53 (dd, J＝10.4, 13.4 Hz, 1H),
2.82 (dd, J＝3.2, 13.4 Hz, 1H), 3.03 (dd, J＝3.5, 8.5 Hz,
1H), 3.09—3.27 (m, 4H), 3.35 (dd, J＝4.8, 10.1 Hz,
1H), 3.51 (d, J＝13.1 Hz, 1H), 3.54 (d, J＝13.1 Hz, 1H),
3.90—3.40 (m, 4H), 5.05 (s, 2H), 6.89 (d, J＝8.6 Hz,
2H), 7.08 (d, J＝8.6 Hz, 2H), 7.25—7.44 (m, 10H); 13C
NMR (CDCl3, 100 MHz) δ: 29.2, 29.7, 32.9, 35.2, 36.0,
38.0, 38.9, 45.9, 49.0, 56.2, 59.8, 60.9, 63.6, 64.2, 64.3,
70.0, 108.1, 114.9, 127.0, 127.4, 127.9, 128.3, 128.5,
129.0, 129.8, 131.6, 137.1, 138.8, 157.2; IR (film) ν:
3396, 2926, 2859, 2786, 1719, 1649, 1513, 1431, 1377,
A solution of I2 (40 mg, 0.15 mmol) in CH2Cl2 (1
mL) was added dropwise to a mixture of amine 11b (50
mg, 0.105 mmol) in CH2Cl2 (0.4 mL) and 5% aqueous
NaHCO3 (1 mL). After stirring for 4 h at room tem-
perature, a 10% aqueous Na2S2O3 (3 mL) was added.
The mixture was extracted with CH2Cl2 (5 mL×4), The
combined organic phases were concentrated under re-
duced pressure to give a diastereomeric mixture of io-
dides 16b, which was used in the next step without fur-
ther purification.
To a solution of the diastereomeric mixture of io-
dides 16b (0.1 mmol) in CH3CN (0.2 mL) were added
benzylmethylamine (32 mg, 0.27 mmol) and K2CO3 (37
mg, 0.27 mmol). The mixture was stirred at 40 ℃
overnight, the suspension was filtered through Celite
and the filtrate was concentrated under reduced pressure.
The residue was purified by chromatography on silica
＋
－1
1237 cm ; MS (ESI ) m/z: 557 (M＋H ). Anal. calcd
for C35H44N2O4: C 75.51, H 7.97, N 5.03; found C 75.16,
H 7.64, N 4.95.
Chin. J. Chem. 2010, 28, 1717— 1724
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Zhang et al.
FULL PAPER
gel [V(PE)∶V(EtOAc)＝10∶1] to afford diamine 17b
(19 mg, 30% from 11b) as a diastereomeric mixture.
To a solution of the diastereomeric mixture of 17b
(400 mg, 0.67 mmol) in THF (0.2 mL) was added a so-
lution of TBAF (1 mol/L in THF, 2 mL). After stirring
for 12 h at room temperature, the reaction was quenched
with water and extracted with EtOAc (3 mL×3). The
combined extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting residue was purified by flash
column chromatography on silica gel eluting with
[V(PE)∶V(EtOAc)＝1∶1] to afford alcohols 18b (192
mg, 60%) and 19b (96 mg, 30%) as colorless oils. 18b:
2H), 2.21 (dd, J＝8.2, 12.5 Hz, 1H), 2.43 (s, 3H), 2.45
(dd, J＝10.4, 13.1 Hz, 1H), 2.65 (dd, J＝8.2, 7.2 Hz,
1H), 2.92 (dd, J＝2.9, 13.1 Hz, 1H), 3.10—3.21 (m,
4H), 3.30 (dd, J＝3.9, 8.9 Hz, 1H), 3.79 (s, 3H), 3.90—
4.00 (m, 4H), 6.81 (d, J＝8.6 Hz, 2H), 7.08 (d, J＝8.6
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 31.6, 32.3,
33.0, 35.2, 35.3, 36.3, 42.1, 49.4, 55.2, 56.0, 57.5, 60.6,
62.3, 64.2, 64.3, 108.0, 113.9, 129.7, 131.0, 158.1; IR
(fil－m) ν: 3393, 2932, 1606, 1511, 1246, 1104, 1033
＋
1
cm ; MS (ESI) m/z: 391 (M＋H ); HRMS (ESI) calcd
for [C22H34N2O4＋H＋] 391.2597, found 391.2607.
(5S)-4-Methyl-2-[(4-methoxyphenyl)methyl]-dispiro-
[1,4-diazabicyclo[3.2.1]oct[2]en-7,1'-cyclohexane-4',
2"-[1,3]dioxepane] (28)
1
[α] 2D0 －8.2 (c 0.8, MeOH); H NMR (CDCl3, 400
MHz) δ: 1.20—1.30 (m, 2H), 1.65—1.85 (m, 6H), 1.87
—1.96 (m, 2H), 2.12 (s, 3H), 2.22 (dd, J＝7.4, 12.3 Hz,
1H), 2.45 (dd, J＝10.1, 12.1 Hz, 1H), 2.80—2.91 (m,
2H), 2.98 (dd, J＝1.0, 12.1 Hz, 1H), 3.10—3.19 (m,
3H), 3.29 (dd, J＝10.9, 16.0 Hz, 1H), 3.47 (d, J＝12.9
Hz, 1H), 3.57 (d, J＝12.9 Hz, 1H), 3.79 (s, 3H), 3.92—
3.97 (m, 4H), 6.83 (d, J＝8.6 Hz, 2H), 7.09 (d, J＝8.6
Hz, 2H), 7.25—7.35 (m, 5H); 13C NMR (CDCl3, 100
MHz) δ: 31.8, 32.2, 33.1, 35.6, 36.3, 40.3, 40.8, 48.1,
55.3, 56.1, 60.4, 60.9, 62.6, 64.2, 64.3, 108.0, 114.0,
127.1, 128.3, 129.2, 129.8, 130.9, 158.1; IR (film)－ν:
Trifluoroacetic anhydride (0.04 mL, 0.298 mmol)
was added to a solution of DMSO (0.05 mL, 0.662
mmol) in 0.8 mL of CH2Cl2 at －78 ℃ and the result-
ing mixture was stirred at －78 ℃ for 20 min. To the
resulting mixture was added a solution of 26 (17 mg,
0.044 mmol) in 0.8 mL of CH2Cl2, and the mixture was
stirred for 30 min. Then Et3N (0.07 mL, 0.53 mmol)
was added and the mixture was allowed to warm to 0
℃, stirred for 30 min and was taken up with 5 mL of
CH2Cl2, which was washed with water and brine and
dried (Na2SO4). After filtration, the solvent was concen-
trated under reduced pressure to give the crude aldehyde
27 as a mixture of diastereomers, which was used in the
next step without further purification.
1
3420, 2935, 2847, 1611, 1511, 1247, 1106, 1034 cm ;
MS (ESI) m/z: 481 (M＋H＋); HRMS (ESI) calcd for
[C29H40N2O4＋H＋] 481.3066, found 481.3077.
19b: [α] 2D0 －35.6 (c 0.4, MeOH); 1H NMR (CDCl3,
400 MHz) δ: 1.30—1.37 (m, 1H), 1.51—1.80 (m, 7H),
2.00 (td, J＝3.9, 13.3 Hz, 1H), 2.15 (s, 3H), 2.31 (dd,
J＝7.5, 13.3 Hz, 1H), 2.53 (dd, J＝10.4, 13.4 Hz, 1H),
2.82 (dd, J＝3.2, 13.4 Hz, 1H), 3.03 (dd, J＝3.6, 8.7 Hz,
1H), 3.09—3.27 (m, 4H), 3.35 (dd, J＝4.8, 10.1 Hz,
1H), 3.51 (d, J＝13.2 Hz, 1H), 3.54 (d, J＝13.2 Hz, 1H),
3.78 (s, 3H), 3.90—4.00 (m, 4H), 6.81 (d, J＝8.6 Hz,
2H), 7.08 (d, J＝8.6 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ: 29.2, 29.7, 32.9, 33.0, 35.3, 36.0, 38.0, 38.9,
46.0, 55.3, 56.3, 59.8, 61.0, 63.6, 64.2, 64.3, 108.2,
113.9, 127.1, 128.3, 129.1, 129.8, 131.3, 158.1; IR (film)
ν: 3389,－2933, 1681, 1512, 1442, 12＋47, 1178, 1106,
To a solution of 27 in 2 mL of MeOH were added
0.8 mL of water and K2CO3 (100 mg, 0.72 mmol). The
reaction was stirred at 25 ℃ for 2 h and concentrated
under reduced pressure. The residue was taken up with
5 mL of CH2Cl2, which was washed with water and
brine and dried (Na2SO4). After filtration, the solvent
was concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica
gel eluting with [V(CH2Cl2)∶V(MeOH)＝60∶1] to
give 28 (9.8 mg, 60%) as a colorless oil. [α] 2D0 ＋10.5
1
(c 0.6, MeOH); H NMR (CDCl3, 400 MHz) δ: 1.45—
1.52 (m, 1H), 1.59—1.80 (m, 6H), 1.85—1.91 (m, 1H),
2.00—2.10 (m, 2H), 2.45 (s, 3H), 2.71 (dd, J＝1.0, 11.4
Hz, 1H), 3.16 (dd, J＝2.2, 11.4 Hz, 1H), 3.22 (s, 2H),
3.28—3.32 (m, 1H), 3.78 (s, 3H), 3.90—4.00 (m, 4H),
5.11 (s, 1H), 6.81 (d, J＝8.6 Hz, 2H), 7.08 (d, J＝8.6
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 29.7, 31.7,
32.5, 33.5, 34.9, 40.4, 41.4, 42.4, 51.6, 55.2, 59.1, 64.3,
72.1, 108.5, 113.6, 114.6, 127.3, 130.1, 132.2, 157.8; IR
(film) ν: －2879, 2851, 2929, 1586, 1510, 1245, 1106,
1
1034 cm ; MS (ESI) m/z: 481 (M＋H ); HRMS (ESI)
calcd for [C29H40N2O4＋H＋] 481.3066, found 481.3076.
3-(4-Methoxyphenyl)-2-(11-methylamino-1,4-dioxa-
9-azadispiro[4.2.4.2]tetradec-9-yl)-propan-1-ol (26)
To a degassed methanolic solution (5 mL) of com-
pound 18b (100 mg, 0.21 mmol) was added 20%
Pd(OH)2/C (50 mg). The mixture was stirred at room
temperature under 101.3 kPa hydrogen pressure for 4 h.
After filtration through Celite, the filtrate was concen-
trated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel
eluting with [V(CH2Cl2)∶V(MeOH)∶V(Et3N)＝10∶
1∶0.1] to afford compound 26 (49 mg, 60%) as a
＋
1
1036 cm ; MS (ESI) m/z: 393 (C22H30N2O3＋Na );
HRMS (ESI) calcd for [C22H30N2O3＋Na＋] 393.2154,
found 393.2140.
Results and discussion
1
colourless oil. [α] D20 －12.0 (c 0.2, MeOH); H NMR
Our synthesis commenced with the preparation of
the O-TBS (O-tert-butyldimethylsilyl) protected
β-amino alcohols 12a and 12b. The building blocks 12a
and 12b were prepared from L-tyrosine by a known
(CDCl3, 400 MHz) δ: 1.22—1.28 (m, 1H), 1.53 (dd, J＝
7.6, 12.5 Hz, 1H), 1.61—1.80 (m, 5H), 1.84—1.93 (m,
1720
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Chin. J. Chem. 2010, 28, 1717— 1724

Enantioselective Synthesis of the Diazatricyclic Core of Alkaloid TAN1251C
procedure11b with minor modification. The key element
resided in running all reactions at 0 ℃ or room tem-
perature to avoid any possible racemization. Thus the
total yield was improved to 40% (for 12a) and 49% (for
12b), respectively.
Scheme 3
compound 14
Unsuccessful iodoaminocyclization reaction of
The requisite homoallylamine 11a was prepared by
the Bonjoch’s one-pot procedure11b with modifications.
Thus, in the presence of 4 Å MS, 1,4-cyclohexanedione
monoethylene acetal reacted with protected amino al-
cohol 12a (CH2Cl2, r.t., overnight) to yield the corre-
sponding imine 13a, which was treated with allylmag-
nesium bromide (Et2O, 0 ℃, 2 h) to give the addition
product 11a in an overall yield of 82%12 (Scheme 2).
Following the same procedure, homoallylamine 11b
was prepared from protected amino alcohol 12b in 83%
yield.
at 40 ℃ overnight to afford the corresponding amine
17a in 44% yield from 11a. It is noteworthy that in or-
der to improve the yield of iodide 16a, iodine solution
in dichloromethane should be slowly added to a sodium
bicarbonate solution of homoallylamine 11a. As indi-
cated by the 1H NMR spectral, azaspirane 17a is a mix-
ture of two diastereomers, and is inseparable by column
chromatography on silica gel. To our satisfaction, when
the tert-butyldimethylsilyl (TBS) group in 17a was
cleaved with TBAF in dichloromethane, alcohols 18a
and 19a were obtained in a ratio of 2∶1 (determined by
1H NMR, combined 90% yield), which are separable by
flash chromatography on silica gel.
Scheme 2 Synthesis of homoallylamines 11a and 11b
To determine the stereochemistries of diastereomers
18a and 19a, their NOESY spectra were recorded.
However, due to both the overlap of signals at δ 3.15
and the free rotation of the C—N bond, we were unable
to determine the stereochemistry of 18a. In contrast, a
correlation between the proton at C-3 (δ 3.20) and one
of the benzylic protons at C-6 (δ 2.53) was observed for
19a (Figure 3). Because C-6 is not in the ring, the ob-
served resonance signals at this carbon reflected an av-
erage result. On the basis of this result, the configura-
tion of C-3 was tentatively assigned as R. To confirm
this reasoning, quantum chemical calculations were
performed. In the optimized stable conformation of 19a
(Figure 4), the nearest distance between the proton at
C-3 and one of the benzylic proton at C-6 was 2.501 Å,
which is within the range of observable NOEs. Fur-
thermore, in the optimized stable conformation of 18a,
the nearest distance between the proton at C-3 and one
of the benzylic protons at C-6 was 4.587 Å, which is at
the marginal to observe NOEs between the two
Reagents and conditions: (a) 1,4-Cyclohexanedione monoethyl-
ene acetal, 4 Å MS, CH2Cl2, r.t., overnight; (b) allylmagnesium
bromide, Et2O, 0 ℃, 2 h, 82% yield (for 11a) and 83% yield (for 11b)
over two steps
With the homoallylamine 11a in hand, we proceeded
to investigate the key iodoaminocyclization reaction.
When amino-olefin 11a was treated with iodine in alka-
line medium, an iodoaminocyclization proceeded
smoothly to provide the 3-iodopyrrolidine 16a. Io-
dine-promoted iodoaminocyclization process has been
employed to form some N-containing ring systems.11
However, Bonjoch and co-workers11b reported that at-
tempt to prepare 15 from homoallylamine 14 by
iodoaminocyclization procedure was unsuccessful due
to the steric hindrance (Scheme 3).
Initial attempts to isolate the iodo-amine product 16a
by silica gel chromatography met with failure, which
was attributed to the lability of the iodo-amine during
the column chromatography. To tackle this problem,
work-up procedure was modified. Thus, after the reac-
tion and work-up, without purification of the resultant
iodo-amine 16a, the mixture was treated with K2CO3 in
CH3CN and allowed to react with methyl benzylamine
Figure 3 Selected NOESY correlation for compounds 18a and
19a.
Chin. J. Chem. 2010, 28, 1717— 1724
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1721

Zhang et al.
FULL PAPER
With the azaspiranes in hand, their cyclizations to
form the tricyclic systems were investigated. To this end,
O-tosylation of 18a was first attempted (p-TsCl, DMAP,
Et3N) (Scheme 5). However, instead of the desired to-
sylation product 20, an unexpected chloride (22) was
obtained in 80% yield, which was presumed to be
formed via the aziridinium intermediate 21.14 The
structure of the chloride 22 was determined by HMBC
technique (Figure 5). The stereochemistry of the newly
formed stereogenic center was not determined.
Scheme 5 Reaction of compound 18a with TsCl
Figure 4 B3LYP/6-31G*-optimized structures for compounds
18a and 19a.
protons. Thus, the stereochemistries of diastereomers
18a and 19a were determined to be those shown in Fig-
ure 3. Because the N-substitution of the system in ana-
log to 16 has been shown to proceed with inversion of
configuration,13 the stereochemistries of the di-
astereomeric 16a were determined as those shown in
Scheme 4.
Scheme 4 Synthesis of 1-azaspiroanes 18 and 19.
Figure 5 Part correlations shown in HMBC spectrum of com-
pound 22.
To overcome this difficulty,
a debenzylation-
cyclization procedure was designed (Scheme 6). Unfor-
tunately, although the concomitant N,O-didebenzylation
under hydrogenolytic conditions gave compound 23 in
60% yield, its cyclization under Ciufolini’s conditions
failed.7c Alternatively, compound 23 was subjected to
oxidation with TFAA-DMSO-Et3N system,15 and the
presumed resultant aldehyde was treated with K2CO3 in
MeOH/H2O, which afforded an unexpected TAN1251C
derivative 25 in a yield of 20%. Presumably, compound
25 was resulted from a rearrangement of the sulfur ylide
formed during the reaction course.16
Reagents and conditions: (a) I2, sat. NaHCO3, CH2Cl2, r.t., 4 h; (b)
BnNHMe, CH3CN, K2CO3, 40 ℃, overnight, yields over two steps
44% for 17a; 30% for 17b; (c) TBAF, THF, r.t., 12 h, 90% (R＝Bn)
and 80% (R＝Me)
1722
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Chin. J. Chem. 2010, 28, 1717— 1724

Enantioselective Synthesis of the Diazatricyclic Core of Alkaloid TAN1251C
Scheme 6 The formation of compound 25
DMSO to yield the aldehyde intermediate 27, which
without further purification, was subjected to hydrolytic
conditions (K2CO3, MeOH/H2O, r.t., 2 h) to give, via
the presumed intermediate 9b, the tricyclic core of
TAN1251C (28) in an overall yield of 60%.
Conclusion
In summary, a new and concise synthetic protocol
has been established for the construction of the di-
azatricyclic core of alkaloid TAN1251C. In contrast to a
literature report, the key I2-promoted intramolecular
iodoaminocyclizations of 11a and 11b preceded
smoothly to give the 1-azaspiro[4,5]decane cores 16a
and 16b, respectively. The formation of the diazatri-
cyclic core 28 was accomplished by oxidation of com-
pound 26 with TFAA/DMSO, followed by treatment
with K2CO3 in MeOH/H2O. Attempted tosylation of 18a
led to an unexpected product 22, which was presumed
to be formed via an aziridinium ion intermediate. Oxi-
dation of compound 23 with TFAA-DMSO-Et3N sys-
tem led to the formation of an unexpected TAN1251C
derivative 25 in 20% yield.
Reagents and conditions: (a) 20% Pd(OH)2/C, H2, MeOH, r.t., 4 h,
60%; (b) PPh3, CCl4, Et3N; (c) TFAA, DMSO, Et3N, CH2Cl2, －78
℃ to 0 ℃, 2 h; (d) K2CO3, MeOH/H2O, r.t., 2 h, 20% from 23
Now it was clear that the free phenol hydroxyl group
in intermediate 23 is unsuitable for the construction of
the desired tricyclic system. We then turned our atten-
tion to investigate the analog of 18a, namely, methyl
aryl ether 18b. Compound 18b was prepared as outlined
in Schemes 3 and 4, and then subjected to hydrogenoly-
sis (101.3 kPa H2, 20% Pd(OH)2/C, MeOH, r.t., 4 h) to
generate the desired secondary amine 26 in 60% yield
(Scheme 7). Compound 26 was oxidized with TFAA/
References
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2
3
Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. WO
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4
5
Ciufolini, M. A. Farmaco 2005, 60, 627.
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(a) Auty, J. M. A.; Churcher, I.; Hayes, C. J. Synlett 2004,
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Scheme 7 Synthesis of the core structure of TAN1251C (28)
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7
For the synthesis of TAN1251B, see ref. 5f.
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9
For the syntheses of TAN1251D, see ref. 5f and 7a.
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(b) TFAA, DMSO, Et3N, CH2Cl2, －78 ℃, 50 min then 0 ℃ 30 min;
(c) K2CO3, MeOH/H2O, r.t., 2 h, 60% from 26
10 For the syntheses of the tricyclic core structure of TAN1251,
see refs. 5a, 5b, 5c, 5e, 5f, 5g, and 7c.
Chin. J. Chem. 2010, 28, 1717— 1724
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Zhang et al.
FULL PAPER
11 For iodine promoted iodoaminocyclization reaction, see:
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12 Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.; Weinreb,
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1724
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Chin. J. Chem. 2010, 28, 1717— 1724