A formal synthesis of a muscarinic M1 receptor antagonist, (-)-TAN1251A

Article abstract of DOI:10.3987/com-03-s(p)14

An aromatic oxidation reaction of a secondary amine, prepared from L-tyrosine and glycine, with hypervalent iodine reagent gave a spirocyclic product, which was further converted into the key intermediate for the synthesis of (-)-TAN1251A.

Full text of DOI:10.3987/com-03-s(p)14

HETEROCYCLES, Vol. 62, 2004, pp. 343 - 355
Received, 30th June, 2003, Accepted, 1st August, 2003, Published online, 14th October, 2003
A FORMAL SYNTHESIS OF A MUSCARINIC M1
RECEPTOR ANTAGONIST, (-)-TAN1251A
Hirotake Mizutani, Jun Takayama, Yukio Soeda, and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
Abstract – An aromatic oxidation reaction of a secondary amine, prepared from
L-tyrosine and glycine, with hypervalent iodine reagent gave a spirocyclic
product, which was further converted into the key intermediate for the synthesis
of (-)-TAN1251A.
TAN1251A(1), B(2), C(3) and D(4), having unique structural features with a 1,4-diazabicyclo-
[3.2.1]octane ring system and a spirocyclic cyclohexanone, were isolated from a Penicillium thomii
RA-89 by Takeda Industries (Figure 1).1 TAN1251A and B exhibit cholinergic activity and inhibit the
acetylcholine-induced contraction of Guinea-pig ileum with ED50 values of 8.0 and 10.0 nM, respectively.
TAN1251A is also known as a selective muscarinic M1 subtype receptor antagonist.2
NMe
NMe
NMe
N
N
N
O
O
O
R
O
O
O
1 TAN1251A (R=H)
2 TAN1251B (R=OH)
4 TAN1251D
3 TAN1251C
Figure 1

The TAN1251 series of compounds contain intriguing structural features and exhibit the attractive
biological activity, which, therefore, led to several total syntheses involving one racemic3 and three chiral
syntheses4 in the past few years. In the latter chiral syntheses, the problematic spirocyclic carbon-nitrogen
bond was constructed by employing a 1,3-dipolar cycloaddition reaction of the chiral nitrone derived from
L-tyrosine leading to the determination of their absolute configuration,4a and by using an N-acylnitrenium
ion intermediate as a reactive species.4b More recently, a new chiral synthetic route of TAN1251A was
achieved starting from trans-hydroxy-L-proline as a chiral source by Kawahara and co-workers.4c We
thought that the carbon-nitrogen bond formation to generate a spirocyclic ring could be achieved by
intramolecular aromatic oxidation of secondary amine5 using hypervalent iodine reagent,6 or an
aminylium ion intermediate generated from the corresponding N-halo compound.7 Herein, we describe
full explanation for our synthesis of optically pure (-)-TAN1251A.8
Based on our retrosynthetic strategy, L-tyrosine was chosen as the starting material, since its chirality
could be transferred into the chiral center of TAN1251A. Moreover, the requisite secondary amine for
aromatic oxidation reaction will readily be obtained by reductive alkylation of a tyrosine derivative with
glycine (Scheme 1).
O
O
O
NMe
NMe
NMe
N
N
N
O
O
O
O
(-)-TAN1251A
O
O
Aromatic
Oxidation
NMe
R N
L-Tyrosine
+
Glycine
N
H
NHMe
CO2Me
BnO
HO
(R=H or halogen)
Scheme 1. Retrosynthetic route for TAN1251A.
The secondary amine as a key intermediate was synthesized from tyrosine methyl ester hydrochloride (5)

as follows. Compound (5) was converted into carbamate (6) by treatment with ethyl chlorocarbonate in
water in the presence of potassium carbonate, in 84% yield. After protection of the phenolic hydroxyl
group of 6 as a benzyl ether in the usual manner, the resulting compound (7) was subjected to lithium
aluminum hydride reduction providing amino alcohol (8) in 81% yield from 6. The secondary amino
group of 8 was then protected as its Boc derivative (9) in 92% yield. Dess-Martin oxidation of primary
alcohol (9) gave aldehyde (10), in 86% yield, which on treatment with glycine methyl ester in the presence
of sodium cyanoborohydride9 gave amine (11) in 87% yield. The Boc group of 11 was deprotected under
acidic condition to afford diamine (12), which, on further treatment with 25% ammonium hydroxide in
ethanol at room temperature gave piperazinone derivative (13) in 88% yield from 11.
CO2Me
CO2Me
OH
i , ii
v
iii , iv
N
NH2 HCl
NHCO2Et
Me
R
BnO
HO
RO
5
6 R=H
8 R=H
7 R=Bn
9 R=Boc
CHO
N
N
H
CO2Me
NH
viii , ix
vi , vii
N
N
BnO
R
RO
Me
Me
BnO
Boc
Me
10
O
11 R=Boc
12 R=H
13 R=Bn
14 R=H
Scheme 2. i: ClCO2Et, K2CO3, H2O, rt (84%); ii: BnBr, K2CO3, DMF, rt (88%); iii: LiAlH4, THF, reflux
(92%); iv: (Boc)2O, K2CO3, THF:H2O(1:1), rt (92%); v: Dess-Martin periodinane, CH2Cl2, 0°C (86%); vi:
glycine methyl ester, NaBH3CN, MeOH, rt (87%); vii: CF3CO2H, CH2Cl2, rt (96%); viii: 25% NH4OH,
EtOH, rt (92%); ix: 10% Pd-C, H2, MeOH, rt (96%)
First, we attempted a carbon-nitrogen bond formation at this stage via an aminylium ion intermediate by
halogenation of 13 with NCS or NBS, followed by treatment with silver(I) oxide7 or the other conditions
[AgBF4,10 Ce(NH4)2(NO2)6, or UV irradiation]. However, none of the desired product could be isolated.
We found that the strategy using the aminylium intermediate was not effective for the formation of the

desired product even with the use of a phenolic compound (14), derived from 13. On the other hand, the
aromatic oxidation reaction of 14 with iodobenzene diacetate in 2,2,2-trifluoroethanol provided the
desired spirocyclic compound (15) in 43% yield. At this point, this oxidation reaction was carried out in
hexafluoroisopropanol as the solvent, and the yield was increased to 69% (Scheme 3). Unfortunately, the
use of iodobenzene ditrifluoroacetate as an oxidizing agent under the same reaction conditions produced a
desired product (15) in less than 10% yield.
O
O
CH3
CH3
NCS
or NBS
Ag2O
N
N
or AgBF4, CAN, UV irrad.
HN
X N
RO
RO
13 R=Bn
14 R=H
X=Cl or Br
PhI(OAc)2
O
O
CH3
CH3
N
N
N
HN
(CF3)2CHOH
0°C, 0.5 h, 69%
O
HO
14
15
Scheme 3. Construction of the spiro-ring system.
In the reduction of dienone (15), difficulties were initially encountered in obtaining the desired products
by hydrogenation with various catalysts, or by hydrogenation after reduction of the carbonyl group. Since
this compound was found to be labile especially to acid conditions taking place a dienone-phenol
rearrangement. In fact, when dienone (15) was subjected to a ketalization, the carbon at the spiro center
was migrated to the β-position of enone producing rearrangement compound (17) as shown in Scheme 4.
Consequently, the carbonyl group could not be protected as an acetal form before hydrogenation reduction.
The structure of 17 was determined by NMR spectral analysis, in which NOEs were observed between the

6- methylene proton and the 7-aromatic proton.
O
O
O
N
Me
Me
catalytic hydrogenation
over several catalysts
N
N
N
acid conditions
Me
5%
N
N
HO
6
7
H
H
H
H
O
O
H+
NOE
6%
15
16
17
Scheme 4. Rearrangement of dienone 15
Fortunately, we found that dienone (15) could be converted to ketone (16) by treatment with 2 equivalent
of triethylsilane11 in the presence of 20 mol% of copper(I) chloride and 20 mol% of dppf in
dichloromethane at 0°C for 36 h in 30% yield, together with enone (18) produced by the partial reduction
of the less hindered olefin of 16,12 in 42% yield. Enone (18) could also be converted to ketone (16) by
further reduction under the same reaction conditions as above in 80% yield. When the reduction of 15 was
carried out with 3 equivalent of triethylsilane, the desired ketone (16) was isolated in 60% yield together
with enone (18) in 9% yield (Scheme 5).
O
O
O
Me
Me
Me
CuCl, dppf
Et3SiH, CH2Cl2
N
N
N
N
N
N
+
0°C to rt, 36 h
O
O
O
15
16
18
CuCl, dppf
Et3SiH, CH2Cl2
O
Me
Me
N
N
HO(CH2)2OH
PPTS, PhH
N
Ref.
N
O
O
O
reflux, 12 h
O
19
TAN1251A
Scheme 5. Reduction of dienone compound.

Finally, protection of ketone (16) with ethylene glycol and a catalytic amount of pyridinium
p-toluenesulfonate in refluxing benzene afforded ketal (19) that is known key intermediate for the
synthesis of (-)-TAN1251A. The spectroscopic data of 19 including its optical rotation {[α]D +15.6° (c
0.71, CHCl3); lit., 4b [α]D +15.2° (CHCl3)} were identical with those reported. Since compound (19) has
already been transformed into (-)-TAN1251A by Wardrop and co-workers,4b this synthesis constitutes its
formal total synthesis.
In conclusion, we have succeeded in a facile synthesis of optically pure (-)-TAN1251A, where aromatic
oxidation reaction of the secondary amine with iodobenzene diacetate was involved as the key reaction.
This synthetic strategy would be applicable to the synthesis of other TAN series of compound, and study
on the synthesis of TAN1251C and D by using tyrosine dimmer as the starting material is in progress.
EXPERIMENTAL
Melting points were measured with a Yanagimoto MP apparatus and are uncorrected. IR spectra were
obtained using a JASCO FT/IR-200 spectrophotometer. 1H- and 13C-NMR spectra were obtained on JEOL
LAMBDA-270 (1H-NMR: 270 MHz, 13C-NMR: 67.8 MHz) instrument for solutions in CDCl3 unless
otherwise noted, and chemical shifts are reported on the δ scale from internal TMS. MS spectra were
measured with a JEOL JMS-D 300 spectrometer. Elemental analyses were performed on a Yanaco-MT5.
L-N-Ethoxycarbonyltyrosine methyl ester (6): To a mixed solution of potassium carbonate (21.5 g,
0.16 mol) in dioxane:H2O (1:1, 200 mL) was added L-tyrosine methyl ester hydrochloride (18.0 g, 77.7
mmol) at 0°C. After stirring for 0.5 h, ethyl chloroformate (8.9 mL, 93.1 mmol) was added to the mixture
and the whole was allowed to stir for 2 h at 0°C. After quenching by addition of 10% HCl, the resulting
mixture was extracted with AcOEt. The extract was washed with brine and dried over Na2SO4. Removal
of volatiles under reduced pressure gave a residue, which was purified by silica gel column
chromatography (CH2Cl2:MeOH, 30:1 v/v) to yield 17.4 g of 6 (84%) as a colorless oil. [α]D23 +51.2° (c
0.96, CHCl3); IR (thin film) cm-1: 3350, 1700, 1520; 1H-NMR (CDCl3) δ: 6.96 (d, J=8.4 Hz, 2H), 6.73 (d,
J=8.4 Hz, 2H), 5.23 (d, J=8.4 Hz, 1H), 4.60 (dd, J=14.2, 6.1 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.72 (s, 3H),

13
2.93-3.09 (m, 2H), 1.22 (t, J=7.1 Hz, 3H); C-NMR δ: 14.4, 37.4, 52.4, 54.9, 61.4, 67.0, 77.2, 115.5,
127.1, 130.3, 155.3, 156.2, 172.5; MS m/z calcd for C13H17NO5 (M+): 267.1106. Found: 267.1094.
Methyl (2S)-3-(4-benzyloxyphenyl)-2-ethoxycarbonylaminopropionate (7): To a solution of 6 (21.5 g,
80.4 mmol) in acetone (200 mL) were added potassium carbonate (22.2 g, 0.16 mol) and benzyl bromide
(10.0 mL, 84.1 mmol) at 0°C, and the resulting mixture was allowed to stir for 12 h at rt. The reaction
mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure.
After addition of AcOEt, the organic layer was washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residual mixture was purified by silica gel column chromatography
(n-hexane:AcOEt, 4:1 v/v) to yield 25.3 g of 7 (88%) as a white solid (mp 61.0~61.7°C). [α]D20 +46.8° (c
0.71, CHCl3); IR (KBr) cm-1: 1720, 1510, 1240; 1H-NMR (CDCl3) δ: 7.29-7.45 (m, 5H), 7.03 (ddd, J=6.6,
8.7, 11.5 Hz, 2H), 6.90 (ddd, J=6.6, 8.7, 11.5 Hz, 2H), 5.09 (d, J=8.1 Hz, 1H), 5.04 (s, 2H), 4.60 (dd,
J=5.6, 8.1 Hz), 4.10 (q, J=7.1 Hz, 2H), 3.71 (s, 3H), 3.04 (d, J=5.6 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H);
13C-NMR δ: 14.5, 37.4, 52.3, 54.7, 61.1, 70.0, 114.9, 127.5, 128.0, 128.6, 130.3, 136.9, 157.9, 172.2; MS
m/z calcd for C20H23NO5 (M+): 357.1576. Found: 357.1582; Anal. Calcd for C20H23NO5: C, 67.21; H,
6.49; N, 3.92. Found: C, 67.30; H, 6.54; N, 3.90.
(2S)-3-(4-Benzyloxyphenyl)-2-methylaminopropan-1-ol (8): To a suspension of lithium aluminum
hydride (6.6 g, 0.17 mol) in THF (300 mL) was added a solution of 7 (25 g, 69.9 mmol) in THF (50 mL)
under argon atmosphere, and the mixture was stirred for 1 h at rt and then stirred for 4 h at reflux
temperature. The reaction was quenched by addition of 1N NaOH at 0°C, and the resulting mixture was
filtered through a pad of Celite. After removal of volatiles of the filtrate under reduced pressure, the
residue was purified by silica gel column chromatography (CH2Cl2:MeOH, 4:1 v/v) to yield 17.6 g of 8
21
(92%) as a white solid (mp 106.0~107.5°C). [α]D +14.8° (c 0.95, CHCl3); IR (KBr) cm-1: 3300, 2890,
1610, 1520, 1250; 1H-NMR (CDCl3) δ: 7.30-7.46 (m, 5H), 7.10 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.6 Hz, 2H),
5.05 (s, 2H), 3.63 (dd, J=3.5, 10.7 Hz, 1H), 3.33 (dd, J=4.6, 10.7 Hz, 1H), 2.61-2.79 (m, 3H), 2.40 (s, 3H),
13
1.91 (br, 2H); C-NMR δ: 33.6, 36.5, 61.8, 62.0, 70.0, 114.9, 127.4, 127.9, 128.5, 130.1, 130.8, 137.0,
157.4; MS m/z calcd for C17H21NO2 (M+): 271.1572. Found: 271.1597; Anal. Calcd for C17H21NO2: C,
75.25; H, 7.80; N, 5.16. Found: C, 74.99; H, 7.74; N, 5.19.

(1S)-3-(4-Benzyloxyphenyl)-2-[(N)-tert-butoxycarbonyl]methylaminopropan-1-ol (9): To a stirred
solution of 8 (17.4 g, 64.1 mmol) in THF:H2O (1:1, 200 mL) were added potassium carbonate (12.4 g,
89.7 mmol) and (Boc)2O (16.8 g, 77.0 mmol) at 0°C, and the mixture was allowed to stir for 12 h at rt.
Citric acid was added to the reaction mixture until the solution became acidic (pH 3) and the resulting
mixture was extracted with AcOEt. The organic layer was washed with saturated solution of aqueous
citric acid and brine, dried over Na2SO4, and concentrated to afford a residue, which was purified by
silica gel column chromatography (n-hexane:AcOEt, 1:1 v/v) to yield 21.8 g of 9 (92%) as a colorless oil.
22
1
[α]D -40.5° (c 1.34, CHCl3); IR (thin film) cm-1: 3420, 2980, 1670, 1510; H-NMR (CDCl3) δ:
7.31-7.44 (m, 5H), 7.09 (br m, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.04 (s, 2H), 3.70 (br m, 2H), 2.67 (br m, 5H),
13
1.41 (s, 9H); C-NMR δ: 28.3, 31.5, 33.8, 34.2, 59.7, 60.1, 62.8, 63.2, 70.0, 80.0, 114.8, 127.4, 127.8,
128.5, 129.8, 130.5, 136.8, 137.0, 156.9, 157.3; MS m/z calcd for C22H29NO4 (M+): 371.2096. Found:
371.2081.
(1S)-3-(4-Benzyloxyphenyl)-2-[(N)-tert-butoxycarbonyl]methylaminopropanal (10): To a solution of
9 (21.0 g, 56.5 mmol) in CH2Cl2 (200 mL) was added Dess-Martin periodinane (30.3 g, 71.4 mmol) at
0°C, and the resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was
filtered through a pad of Celite, and the filtrate was concentrated to give a residue, which was purified by
silica gel column chromatography (n-hexane:AcOEt, 2:1 v/v) to yield 17.9 g of 10 (86%) as a colorless
23
1
oil. [α]D -97.9° (c 0.41, CHCl3); IR (thin film) cm-1: 2980, 1780, 1520; H-NMR (CDCl3) δ: 9.65 (s,
1H), 7.29-7.45 (m, 5H), 7.09 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 5.04 (s, 2H), 4.16 (dd, J=4.8,
10.2 Hz, 0.45H), 3.94 (dd, J=4.0, 10.2 Hz, 0.55H), 3.24 (dd, J=4.6, 14.3 Hz, 1H), 2.80-2.99 (m, 1H), 2.63
13
and 2.68 (each s, 3H), 1.38-1.43 (each s, 9H); C-NMR δ: 28.1, 28.2, 31.8, 32.6, 34.6, 35.0, 68.3, 69.5,
69.9, 80.4, 81.1, 114.9, 115.0, 127.3, 127.8, 128.5, 129.7, 130.0, 130.6, 136.9, 157.5, 198.9, 199.4; MS
m/z calcd for C22H27NO4 (M+): 369.1940. Found: 369.1961.
Methyl
N-[(2S)-3-(4-benzyloxyphenyl)-2-(tert-butoxycarbonylmethylamino)propyl]aminoacetate
(11): To a solution of NaBH3CN (2.64 g, 42.0 mmol) and glycine methyl ester hydrochloride (10.5 g, 88.4
mmol) in MeOH (200 mL) was added slowly a solution of 10 (15.5 g, 42.0 mmol) in MeOH (30 mL) at
0°C, and the mixture was stirred for 4 h at the same temperature. The reaction mixture was quenched by

saturated solution of aqueous NaHCO3, and the resulting mixture was extracted with CHCl3:MeOH (9:1).
The organic layer was washed with brine, dried over Na2SO4, and concentrated to afford a residue, which
was purified by silica gel column chromatography (CH2Cl2:MeOH, 20:1 v/v) to yield 16.2 g of 11 (87%)
24
1
as a colorless oil. [α]D -15.1° (c 0.43, CHCl3); IR (thin film) cm-1: 2980, 1740, 1690, 1510; H-NMR
(CDCl3) δ: 7.26-7.44 (m, 5H), 7.03-7.12 (m, 2H), 6.88 (d, J=8.6 Hz, 2H), 5.03 (s, 2H), 4.31-4.46 (br m,
1H), 3.72 (br s, 3H), 3.42 (q, J=17.5 Hz, 2H), 2.71-2.85 (m, 2H), 2.67 and 2.77 (each s, 3H), 2.61 (dd,
J=4.9, 12.2 Hz, 2H), 1.30 and 1.37 (each s, 9H); 13C-NMR δ: 28.2, 28.9, 35.9, 49.9, 50.2, 50.3, 51.6, 55.8,
57.1, 69.9, 77.2, 79.4, 114.7, 127.3, 127.8, 128.4, 129.8, 130.7, 137.0, 156.0, 157.3, 172.6; MS m/z calcd
for C25H34N2O5 (M+): 442.2467. Found: 442.2463; Anal. Calcd for C25H34N2O5: C, 67.85; H, 7.74; N,
6.33. Found: C, 67.57; H, 7.79; N, 6.21.
Methyl N-[(2S)-3-(4-benzyloxyphenyl)-2-methylaminopropyl]aminoacetate (12): To a solution of 11
(15.0 g, 33.9 mmol) in CH2Cl2 (150 mL) was added slowly trifluoroacetic acid (13 mL, 0.17 mol) at 0°C,
and the resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated under reduced
pressure to give a residue, which was purified by silica gel column chromatography (CH2Cl2:MeOH, 15:1
v/v) to yield 11.1 g of 12 (96%) as a colorless oil. [α]D24 -15.1° (c 0.43, CHCl3); IR (thin film) cm-1: 2980,
1740, 1690, 1510; 1H-NMR (CDCl3) δ: 7.29-7.65 (m, 5H), 7.12 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H),
5.03 (s, 2H), 3.68 (s, 3H), 3.32 (d, J=18.0 Hz, 1H), 3.49 (d, J=18.0 Hz, 1H), 2.79-3.17 (m, 5H), 2.73 (s,
3H); 13C-NMR δ: 30.6, 33.7, 47.9, 50.0, 51.8, 60.4, 69.8, 115.1, 127.3, 127.7, 127.8, 128.4, 130.0, 136.7,
157.8, 173.1; MS m/z calcd for C25H34N2O5 (M+): 442.2467. Found: 442.2463; Anal. Calcd for
C25H34N2O5: C, 67.85; H, 7.74; N, 6.33. Found: C, 67.57; H, 7.79; N, 6.21.
(6S)-6-(4-Benzyloxybenzyl)-1-methylpiperazin-2-one (13): To a mixed solution of ammonium
hydroxide (25%, 50 mL) and EtOH (80 mL) was added slowly a solution of 12 (10.5 g, 30.7 mmol) in
EtOH (50 mL) at 0°C, and the whole was stirred for 12 h at rt. The reaction mixture was concentrated
under reduced pressure. The residual mixture was extracted with CH2Cl2, and the organic layer was
washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. After removal of volatiles
under reduced pressure, the residue was purified by silica gel column chromatography (CH2Cl2:MeOH,

40:1 v/v) to yield 8.6 g of 13 (92%) as a white solid (mp 145~146°C). [α]D24 +33.4° (c 0.54, CHCl3); IR
(KBr) cm-1: 3300, 1640, 1510, 1250; 1H-NMR (CDCl3) δ: 7.29-7.45 (m, 5H), 7.09 (ddd, J=6.6, 8.6, 11.5
Hz, 2H), 6.93 (ddd, J=6.6, 8.6, 11.5 Hz, 2H), 5.05 (s, 2H), 3.47 (s, 2H), 3.29-3.41 (m, 1H), 3.04 (s, 3H),
13
2.84-3.02 (m, 4H), 1.55 (br s, 1H); C-NMR δ: 33.3, 36.4, 45.2, 49.9, 60.3, 69.9, 115.1, 127.4, 127.9,
128.5, 129.8, 130.1, 136.8, 157.6, 168.4; Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.03. Found:
C, 73.39; H, 7.27; N 8.93.
(6S)-6-(4-Hydroxybenzyl)-1-methylpiperazin-2-one (14): To a stirred solution of 13 (4.0 g, 12.9 mmol)
in MeOH (70 mL) was added 10% Pd on carbon (400 mg, 10% based on 13), and the mixture was
allowed to stir for 2 h at rt under H2 atmosphere. The reaction mixture was filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure and residual mixture was purified by silica gel
column chromatography (CH2Cl2:MeOH, 6:1 v/v) to yield 2.7 g of 14 (96%) as a white solid (mp
24
1
206.5~207.8°C). [α]D +45.7° (c 0.95, EtOH); IR (KBr) cm-1: 3120, 2950, 2320, 1620, 1510; H-NMR
(CD3OD) δ: 7.06 (ddd, J=6.4, 8.4, 11.4 Hz, 2H), 6.74 (ddd, J=6.4, 8.4, 11.4 Hz, 2H), 3.46 (ddd, J=5.8, 9.4,
13.5 Hz, 1H), 3.35 (s, 2H), 3.31 (quint, J=1.6 Hz, 1H), 3.04 (dd, J=4.3, 13.5 Hz, 1H), 3.00 (s, 3H),
13
2.76-2.91 (m, 3H); C-NMR δ: 33.9, 37.1, 45.3, 49.7, 61.4, 116.5, 129.5, 131.4, 157.4, 170.8; MS m/z
calcd for C12H17N2O2 (M+): 221.1302. Found: 221.1290; Anal. Calcd for C12H16N2O2: C, 65.43; H, 7.32;
N, 12.72. Found: C, 65.20; H, 7.43; N, 12.49.
(5S)-Spiro{4-methyl-1,4-diazabicyclo[3.2.1]octan-3-one-7,1’-cyclohexa-2’,5’-dien-4’-one} (15): To a
solution of iodobenzene diacetate (1.10 g, 3.42 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (40 mL) was
added dropwise a solution of 14 (0.70 g, 3.18 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL) at 0°C
and the resulting mixture was allowed to stir for 1 h at the same temperature. After removal of volatiles,
the residual mixture was purified by silica gel column chromatography (CH2Cl2:MeOH, 25:1 v/v) to yield
0.48 g of 15 (69%) as a white solid (mp 124.5~126.2°C). [α]D20 -23.52° (c 0.53, CHCl3); IR (KBr) cm-1:
1
2970, 1670, 1630; H-NMR (CDCl3) δ: 6.82-6.76 (m, 2H), 6.29 and 6.14 (each distorted d, J=9.7 Hz,
each 1H), 3.93 (dd, J=4.1, 2.8 Hz, 1H), 3.75 (d, J=18.5 Hz, 1H), 3.58 (dd, J=18.5, 1.5 Hz, 1H), 3.46 (dd,
J=12.7, 3.0 Hz, 1H), 3.20 (br d, J=12.7 Hz, 1H), 3.00 (s, 3H), 2.30 (dd, J=13.8, 2.8 Hz, 1H), 2.11 (dd,

13
J=13.8, 4.1 Hz, 1H); C-NMR (CDCl3) δ: 33.6, 45.1, 57.2, 58.1, 60.7, 63.4, 124.9, 129.3, 146.6, 149.9,
166.8, 184.8; MS m/z calcd for C12H14N2O2 (M+): 218.1069. Found: 218.1055.
(5S)-Spiro{4-methyl-1,4-diazabicyclo[3.2.1]octan-3-one-7,1’-cyclohexan-4’-one}
(16)
and
(5S,7S)-Spiro{4-methyl-1,4-diazabicyclo[3.2.1]octan-3-one-7,1’-cyclohex-2’-en-4’-one} (18): To a
solution of 15 (200 mg, 0.92 mmol) in CH2Cl2 (10 mL) were added CuCl (18.1 mg, 0.18 mmol), sodium
tert-butoxide (24.6 mg, 0.26 mmol) and dppf (101.6 mg, 0.18 mmol) under argon atmosphere. After
stirring for 15 min at 0°C, triethylsilane (0.44 mL, 2.75 mmol) was added dropwise to the mixture at 0°C,
and the whole was allowed to stir for 36 h at rt. The reaction mixture was quenched by addition of brine,
and then extracted with CH2Cl2. The extract was washed with brine and dried over Na2SO4. After removal
of volatiles under reduced pressure, the residual mixture was purified by silica gel column
chromatography to yield 121 mg of 16 (60%) as a white solid (mp 98.5~99.5°C) as the first eluent, and 19
22
mg of 18 (9%) as colorless needles (mp 92.0~93.0°C) as the second eluent. 16: [α]D +8.73° (c 0.90,
CHCl3); IR (KBr) cm-1: 2955, 1715, 1646; 1H-NMR (CDCl3) δ: 3.70 (d, J=18.5 Hz, 1H), 3.69 (dd, J=4.4,
2.5 Hz, 1H), 3.33 (dd, J=12.5, 2.5 Hz, 1H), 3.14 (br d, J=12.5 Hz, 1H), 2.76 (ddd, J=14.5, 11.0, 5.4 Hz,
13
1H), 2.52-2.18 (m, 3H), 2.17-1.93 (m, 4H), 1.88-1.55 (m, 2H); C-NMR (CDCl3) δ: 33.2, 34.5, 38.1,
38.5, 38.6, 45.3, 55.1, 56.4, 59.7, 63.6, 167.5, 210.1; Anal. Calcd for C12H18N2O2: C, 64.84; H, 8.16; N,
12.60. Found: C, 64.92; H, 8.20; N, 12.51. 18: [α]D20 +96.0° (c 0.38, CHCl3); IR (KBr) cm-1: 2960, 1678,
1646; 1H-NMR (CDCl3) δ: 6.64 (dd, J=10.1, 2.0 Hz, 1H), 6.05 (dd, J=10.1, 1.0 Hz, 1H), 3.79 (dd, J=4.3,
2.6 Hz, 1H), 3.62 (d, J=18.5 Hz, 1H), 3.47 (dd, J=18.5, 1.6 Hz, 1H), 3.33 (dd, J=12.4, 2.6 Hz, 1H), 3.05
(m, 1H), 2.97 (s, 3H), 2.90 (ddd, J=16.8, 13.0, 4.9 Hz, 1H), 2.41-2.32 (m, 1H), 2.27 (dd, J=13.7, 2.6 Hz,
1H), 2.10-2.01 (m, 1H), 1.95 (dd, J=13.0, 3.8 Hz, 1H), 1.85 (dd, J=13.7, 4.3 Hz, 1H); 13C-NMR (CDCl3)
δ: 33.4, 35.4, 36.1, 48.3, 56.6, 57.1, 61.0, 63.4, 130.9, 150.9, 167.2, 198.9; MS m/z calcd for C12H16N2O2
(M+): 220.1212. Found: 220.1204.
(5S)-8-Hydroxy-4-methyl-5,6-dihydro-4H-1,5-methanobenzo[e][1,4]diazocin-3-one (17): To a stirred
solution of 15 (40 mg, 0.18 mmol) in benzene (2 mL) were added a catalytic amount of pyridinium
p-toluenesulfonate, MgSO4 (40 mg) and ethylene glycol (0.5 mL), and the mixture was stirred for 6 h at
reflux temperature. The reaction mixture was concentrated under reduced pressure to afford a residue,

which was purified by silica gel column chromatography (CH2Cl2:MeOH, 12:1 v/v) to yield 30.8 mg of
28
17 (77%) as a colorless needles (mp 264~267°C). [α]D -50.9° (c 0.18, MeOH); IR (KBr) cm-1: 3430,
1
3150, 1618, 1605, 1520, 1440, 1250, 1045, 862; H-NMR (CDCl3) δ: 6.88 (d, J=8.6 Hz, 1H), 6.62 (dd,
J=8.6, 2.8 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 3.86 (d, J=17.5 Hz, 1H), 3.79 (m, 1H), 3.52-3.61 (m, 1H),
3.45 (dd, J=17.5, 1.8 Hz, 1H), 3.31 (m, 1H), 3.19 (d, J=13.4 Hz, 1H), 2.91-3.06 (m, 5H); 13C-NMR
(CDCl3: 125.7 Hz) δ: 32.8, 33.8, 50.5, 52.7, 61.8, 116.0, 117.0, 127.1, 128.8, 140.7, 155.8, 170.6; MS m/z
calcd for C12H14N2O2 (M+): 218.1068. Found: 218.1055.
(5”S)-Dispiro{4-methyl-1,4-diazabicyclo[3.2.1]octan-3-one-7,1’-cyclohexane-4’,2”-1”,3”-dioxolane}
(19): To a stirred solution of 16 (44 mg, 2.00 µmol) in benzene (4 mL) were added a catalytic amount of
pyridinium p-toluenesulfonate and ethylene glycol (0.5 mL), and the mixture was stirred for 12 h at reflux
temperature equipped with Dean-Stark condenser. After quenching by addition of saturated aqueous
NaHCO3, the resulting mixture was extracted with CHCl3. The extract was washed with brine, dried over
Na2SO4, and concentrated to afford a residue, which was purified by silica gel column chromatography
(CH2Cl2:MeOH, 30:1 v/v) to yield 34.7 mg of 19 (66%) as a colorless oil. [α]D20 +15.6° (c 0.71, CHCl3);
IR (thin film) cm-1: 2950, 2930, 2890, 1644, 1154; 1H-NMR (CDCl3) δ: 3.88 (br s, 4H), 3.55-3.49 (m, 2H),
3.41 (d, J=18.6 Hz, 1H), 3.18 (dd, J=12.2, 2.6 Hz, 1H), 2.98 (d, J=12.2 Hz, 1H), 2.83 (s, 3H), 1.86-1.62
(m, 7H), 1.60-1.42 (m, 3H); 13C-NMR (CDCl3) δ: 31.8, 32.5, 32.7, 33.3, 36.4, 45.0, 55.0, 56.3, 59.9, 64.1,
64.2, 64.2, 107.9, 168.2; MS m/z calcd for C14H22N2O3 (M+): 266.1630. Found: 266.1623.
ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
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