Total synthesis of antimuscarinic alkaloid, (±)-TAN1251A

Article abstract of DOI:10.1016/S0040-4020(02)00436-2

The total synthesis of (±)-TAN1251A possessing an antimuscarinic activity was achieved. Carboxylic acid (1) was converted into carbamate (3) through a sequence of alkylation and Curtius rearrangement. After a few functional group interconversions of 3, the corresponding amine (9) was converted into an azaspiro molecule (18) through cyclization and installation of a C₂ unit. Hydrolysis of 18 followed by lactam formation afforded tricyclic compound (20). Coupling of 20 with aldehyde (22) gave two epimeric adducts, (23A) and (23B), which were converted into TAN1251A by four steps.

Full text of DOI:10.1016/S0040-4020(02)00436-2

TETRAHEDRON
Pergamon
Tetrahedron 58 ,2002) 4917±4924
Total synthesis of antimuscarinic alkaloid, ꢀ^)-TAN1251A
²
Shinji Nagumo,p Atsushi Nishida, Chikako Yamazaki, Aoi Matoba, Kikue Murashige
and Norio Kawaharap
Hokkaido College of Pharmacy, Katsuraoka 7-1, Otaru 047-0264, Japan
Received 27February 2002; accepted 15 April 2002
AbstractÐThe total synthesis of ,^)-TAN1251A possessing an antimuscarinic activity was achieved. Carboxylic acid ,1) was converted
into carbamate ,3) through a sequence of alkylation and Curtius rearrangement. After a few functional group interconversions of 3, the
corresponding amine ,9) was converted into an azaspiro molecule ,18) through cyclization and installation of a C2 unit. Hydrolysis of 18
followed by lactam formation afforded tricyclic compound ,20). Coupling of 20 with aldehyde ,22) gave two epimeric adducts, ,23A) and
,23B), which were converted into TAN1251A by four steps. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
TAN1251 A, B, C and D are alkaloids isolated from a
culture of Penicillium thomii RA-89.1 These compounds
show the inhibition activity toward a muscarinic acetyl-
choline receptor. In particular, the af®nity of TAN1251B
is stronger than that of atropine. TAN1251A shows selective
inhibition toward the M1 subtype of the muscarinic receptor.
The structures involve unique tricyclic skeleton that consists
of a 1,4-diazabicyclo[3.2.1]octane ring and a cyclohexa-
none ring through a spiro bond. In the case of TAN1251A
and B, the skeleton is linked to a long side chain through a
Z-double bond. The unique structure and characteristic
biological property attracted the interest of organic chemist.
This report describes full explanation for our total synthesis
of racemic TAN1251A.2,3
2. Results and discussion
Scheme 1 shows the retrosynthetic analysis of TAN1251A.
The target molecule should be obtained by aldol reaction of
tricyclic lactam ,20) with aromatic aldehyde and subsequent
functional group interconversions. The key intermediate 20
might be prepared from an azaspirocyclic molecule ,10) via
installation of an acetic acid unit. Disconnection of the
pyrrolidine ring in 10 leads to carbamate ,3). Miller et al.
have reported the ef®cient conversion of cyclohexyl-
carboxylic acid into cyclohexylamine methylcarbamate
through a sequence of alkylation and Curtius rearrange-
ment.4 Thus, we selected carboxylic acid ,1) as a starting
material.
Compound 1 was synthesized from p-hydroxybenzoic acid
according to the reported procedure.5 The ®rst subject was
the introduction of an alkyl chain and an amino group into
the cyclohexanone ring. Treatment of 1 with two equiva-
lents of lithium diisopropylamide ,LDA) and allyl bromide
gave the desired product ,2) in high yield. Curtius rearran-
gement of 2 showed a satisfactory result in the case of using
diphenylphosphoryl azide ,DPPA). Treatment of 2 with
DPPA in re¯uxing benzene followed by addition of benzyl
alcohol gave urethane compound 3 in 65% yield.4,6 Next, we
carried out the construction of a pyrrolidine ring. Our initial
Keywords: TAN1251A; antimuscarinic activity; aldol reaction; Curtius
rearrangement.
p
Corresponding authors. Tel.: 181-134-62-1842; fax: 181-134-62-5161;
e-mail: nagumo@hokuyakudai.ac.jp
Present address: Faculty of Pharmaceutical Sciences, Chiba University,
1-33 Yayoi-cho, Inage-ku, Chiba-shi 263-8522, Japan.
²
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00436-2

4918
S. Nagumo et al. / Tetrahedron 58 *2002) 4917±4924
Scheme 1.
Scheme 2.
plan led us to select the ring formation of epoxide ,6) as a
key step. Treatment of 3 with a catalytic amount of osmium
tetroxide and an equivalent of N-methylmorpholine N-oxide
,NMO) as oxidants gave diol ,4) in high yield. When 4 was
subjected to tosylation by using one equivalent of p-toluene-
sulfonyl chloride ,TsCl), primary alcohol was selectively
tosylated to give 5 in 86% yield. Treatment of 5 with
K2CO3 in methanol afforded the desired product 6 in 91%
yield. The cyclization of 6 upon treatment with potassium
tert-butoxide in THF and DMSO afforded cyclic compound
,7) in 38% yield. The cyclization was carried out by other
procedures, but there was no increase in yield ,Scheme 2).
poor nucleophilicity of carbamate nitrogen and the dis-
advantageous cyclization mode in view of Baldwin's
rule.7 Thus, aminotosylate 9 was expected to be more suited
for the construction of a pyrrolidine ring. Silylation of 5
afforded 8 in 92% yield. Catalytic hydrogenolysis of 8
proceeded smoothly to give 9. Without puri®cation, 9 was
excellently cyclized by treatment with 1,8-diazabicyclo-
[5.4.0]undec-7-ene ,DBU) in re¯uxing benzene. Cyclized
compound 10 was further protected by a BOC group, and
the resulting product was desilylated to give alcohol ,12) in
72% yield from 8 ,Scheme 3).
The most important step in our synthesis of TAN1251A was
the construction of a piperazine ring. Our ®rst attempt at
The dif®culty in the cyclization might be attributed to the
Scheme 3.

S. Nagumo et al. / Tetrahedron 58 *2002) 4917±4924
4919
Aldol reaction of 20 with aldehyde ,22)10 was carried out by
using LDA in THF at 2788C to form two adducts ,23A ,less
polar)) ,36%) and ,23B ,more polar)) ,49%). These
compounds were easily separated by column chromato-
1
graphy with silica gel. The H NMR of 23A showed a
benzylic proton peak at 4.96 ppm ,d, Jˆ7.8 Hz) and two
bridgehead methylene proton peaks at 3.12 ppm ,d,
Jˆ12.5 Hz) and 2.76 ppm ,d, Jˆ12.5 Hz), while that of
23B exhibited a benzylic proton peak at 4.77 ppm ,d,
Jˆ7.3 Hz) and two bridgehead methylene proton peaks at
3.29 ppm ,d, Jˆ12.0 Hz) and 2.82 ppm ,d, Jˆ12.0 Hz).
Their con®gurations at the a position of the amide group
were assigned by observation of NOEs between the bridge-
head proton peak and the benzylic proton peak. It was
concluded that 23A and 23B were epimers at the bezylic
position. The result demonstrated that 22 attacked enolate
Scheme 4.
Scheme 5.
constructing a piperazine ring was the cyclization of
tosylate ,14). Deprotection of 12 with tri¯uoroacetic acid
,TFA) followed by alkylation with iodoacetamide under
alkaline conditions gave an N-alkylated product ,13).
Treatment of 13 with TsCl provided 14 in 72% yield. Unfor-
tunately, cyclization of 14 by treatment with several bases
did not give any desired compound ,Scheme 4).
The construction of a piperazine ring was successfully
achieved by the following procedure. Without
puri®cation, 10 was alkylated with ethyl bromoacetate in
the presence of potassium carbonate, and the resulting
ester ,15) was desilylated to give alcohol ,16) in high
yield. Treatment of 16 with DPPA8 followed by
hydrogenolysis provided amine ,18). Hydrolysis of 18
with lithium hydroxide followed by cyclization with
DPPA and Et3N in DMF afforded the desired product ,19)
in 50% overall yield.9 Treatment of 19 with methyl iodide
in the presence of sodium hydride provided methylated
compound ,20) in 56% yield. The low yield of 20
would be attributed to competitive methylation of
tertiary amine undertaking decomposition of the skeleton
,Scheme 5).
Figure 1. The optimized structure of the enolate anion 21. Black, carbon;
white, hydrogen; blue, nitrogen, red, oxygen.

4920
S. Nagumo et al. / Tetrahedron 58 *2002) 4917±4924
Figure 2. ,A) D Heat of formationˆ0 kcal/mol; ,B) D heat of formationˆ4.7kcal/mol.
Scheme 6.
,21) from the b-face. The conformation of 21 was optimized
by semi-empirical molecular orbital calculation using AM1
hamiltonian as shown in Fig. 1.11 The stereoselectivity
3. Experimental
3.1. General methods
might be due to a shielding of the a-face of 21 by the
cyclohexanone ring. The con®guration at the benzylic
position of the respective compounds was not determined.
Interestingly, mesylation of 23A and 23B followed by treat-
The melting points were determined on Yanagimoto micro
melting point apparatus and were uncorrected. IR spectra
were recorded on JASCO IRA-2 spectrometer. NMR
spectra were recorded on a JEOL GX-270 spectrometer
using tetramethylsilane as an internal standard. Chemical
shifts are given in ppm. The following abbreviations are
used: sˆsinglet, dˆdoublet, tˆtriplet, qˆquartet,
mˆmultiplet, brˆbroad. MS spectra were measured on a
Hitachi M-2000 spectrometer. Column chromatography
was carried out on Merck's Silica gel 60 ,70±230 mesh
ASTM) or Wako's Florisil ,100±200 mesh). All experi-
ments except for dihydroxylation of 3 and hydrolyses of
18 and 25 were performed under anhydrous conditions
under Ar atmosphere.
t
ment with BuOK gave enone ,24)12 in 82 and 64% yield,
respectively. The stereochemical result of these elimination
should be due to the pass way including a benzylic cation
,E1 elimination). Semi-empirical molecular orbital calcula-
tion using AM1 hamiltonian showed that cation A is more
stable than cation B ,Fig. 2).11 Reduction of 24 with AlH3
prepared from LiAlH4 and AlCl3 provided enamine ,25),13
which was deprotected by hydrolysis with 1N HCl in
acetone to afford TAN-1251A in 40% yield from 24. Spec-
troscopic data of the synthetic material were identical with
those of the natural product ,Scheme 6).1

S. Nagumo et al. / Tetrahedron 58 *2002) 4917±4924
4921
3.1.1.
8-ꢀ20-Propenyl)-1,4-dioxaspiro[4.5]decane-8-
4-,N,N-dimethylamino)pyridine ,122 mg, 1.00 mmol). The
mixture was stirred at room temperature for 4 h, then
quenched with saturated aqueous NaCl, and extracted with
AcOEt. The extract was dried over MgSO4 and concentrated
under reduced pressure. The residue was puri®ed by column
chromatography on silica gel eluted with hexane/AcOEt
,1:2) to give 5 ,4.46 g, 8.59 mmol, 86%) as a colorless oil.
1H NMR ,CDCl3) d: 1.51±1.88 ,8H, m), 2.07±2.24 ,2H, m),
2.45 ,3H, s), 2.55 ,1H, br s), 3.81±4.10 ,7H, m), 4.76 ,1H, br
s), 5.02 ,2H, s), 7.28±7.39 ,7H, m), 7.78 ,2H, d, Jˆ8.4 Hz).
13C NMR ,CDCl3) d: 21 ,q), 30.3 ,t), 30.4 ,t), 32.7,t), 33.3
,t), 41 ,t), 53 ,s), 64.2 ,t), 64.3 ,t), 66.3 ,d), 66.4 ,t), 74 ,t),
102 ,s), 128.0 ,d£4), 128.1 ,d), 128.5 ,d£2), 130 ,d£2), 133
,s), 136 ,s), 145 ,s), 155 ,s). IR ,CHCl3) cm21: 3450, 1720,
1600. EI-MS m/z: 347,M 12TsOH), 101, 91. To a solution
of 5 ,11.1 g, 21.4 mmol) in MeOH ,40 ml) was added
K2CO3 ,3.90 g). The mixture was stirred for 1 h at room
temperature, then concentrated under reduced pressure,
quenched with saturated aqueous NH4Cl, and extracted
with AcOEt. The extract was dried over MgSO4 and concen-
trated under reduced pressure. The residue was puri®ed by
column chromatography on silica gel eluted with hexane/
AcOEt ,1:1) to give 6 ,6.75 g, 19.5 mmol, 91%) as a color-
less oil. 1H NMR ,CDCl3) d: 1.52±1.82 ,8H, m), 2.07±2.33
,2H, m), 2.40 ,1H, dd, Jˆ5.1, 2.8 Hz), 2.70 ,1H, dd, Jˆ5.1,
4.1 Hz), 2.96 ,1H, m), 3.94 ,4H, s), 4.74 ,1H, br s), 5.06
,2H, s), 7.28±7.42 ,5H, m). IR ,neat) cm21: 3350, 1720,
1705. HR-MS m/z: calcd for C19H25NO5 347.1731; found
347.1720.
carboxylic acid ꢀ2). To a solution of diisopropylamine
,16.6 g, 164 mmol) in THF ,150 ml) were successively
added 1.63 M-BuLi in hexane ,102 ml, 166 mmol) and a
solution of 1 ,12.4 g, 66.7mmol) in THF ,40 ml) at 0 8C.
The mixture was stirred for 1 h at room temperature. After
the mixture was cooled to 08C, allyl bromide ,13.5 ml,
156 mmol) was added. The reaction mixture was further
stirred for 2 h at room temperature, then quenched with
saturated aqueous NH4Cl, and extracted with AcOEt. The
extract was dried over MgSO4 and concentrated under
reduced pressure. The residue was puri®ed by column chro-
matography on silica gel eluted with AcOEt to give 2
,11.8 g, 52.2 mmol, 78%) as a colorless oil. 1H NMR
,CDCl3) d: 1.40±2.60 ,8H, m), 2.32 ,2H, d, Jˆ7.4 Hz),
3.94 ,4H, s), 5.02±5.14 ,2H, m), 5.75 ,1H, m). IR
,neat) cm21: 3600±2400, 1700, 1640. EI-MS m/z: 226
,M1), 211, 198, 184, 169, 157, 149, 139, 126. HR-MS
m/z: calcd for C12H18O4 226.1204; found 226.1222.
3.1.2. 8-Phenylmethoxycarbonylamino-8-ꢀ20-propenyl)-
1,4-dioxaspiro[4.5]decane ꢀ3). A mixture of 2 ,5.00 g,
22.1 mmol), triethylamine ,7.7 ml, 55.3 mmol), diphenyl-
phosphoryl azide ,7.2 ml, 33.2 mmol) and benzene
,70 ml) was re¯uxed for 30 min. After addition of benzyl
alcohol ,22.9 ml, 221 mmol) at room temperature, the reac-
tion mixture was further re¯uxed for 5 h and concentrated
under reduced pressure. The residue was puri®ed by column
chromatography on silica gel eluted with hexane/AcOEt
,5:1) to give 3 ,4.72 g, 14.3 mmol, 65%) as a colorless oil.
1H NMR ,CDCl3) d: 1.58±1.71 ,6H, m), 2.02±2.09 ,2H, m),
2.48 ,2H, d, Jˆ7.4 Hz), 3.93 ,4H, s), 4.53 ,1H, s), 4.99±5.09
,4H, m), 5.67,1H, ddt, Jˆ16.8, 10.2, 7.4 Hz), 7.26±7.42
,5H, m). IR ,neat) cm21: 3300, 1725, 1710, 1640. EI-MS
m/z: 331 ,M1), 290, 246. HR-MS m/z: calcd for C19H25NO4
331.1782; found 331.1754.
3.1.5. Dispiro[1,3-dioxolane-2,10-cyclohexane-40,500-3-hy-
droxy-1-phenylmethoxycarbonylpyrrolidine] ꢀ7). To a
solution of potassium tert-butoxide ,43.0 mg, 0.384 mmol)
in THF ,0.25 ml) and dimethylsulfoxide ,0.25 ml) was
added a solution of 6 ,86.5 mg, 0.249 mmol) in THF
,0.5 ml). The reaction mixture was stirred for 5.5 h at
room temperature, then quenched with saturated aqueous
NH4Cl, and extracted with AcOEt. The extract was washed
with saturated aqueous NaCl and dried over MgSO4 and
concentrated under reduced pressure. The residue was
puri®ed by column chromatography on ¯orisil eluted with
hexane/AcOEt ,1:1) to give 7 ,33.0 mg, 0.095 mmol, 38%)
as a colorless oil. 1H NMR ,CDCl3) d: 1.40±1.78 ,8H, m),
1.90±2.06 ,2H, m), 2.19 ,1H, td, Jˆ12.4, 4.4 Hz), 3.64 ,1H,
dd, Jˆ12.2, 5.4 Hz), 3.80 ,1H, dd, Jˆ12.2, 3.0 Hz), 3.92±
4.00 ,4H, m), 4.33 ,1H, m), 5.10 ,2H, s), 7.28±7.42 ,5H, m).
IR ,neat) cm21: 3350, 1670. EI-MS m/z: 347,M 1), 101, 91.
HR-MS m/z: calcd for C19H25NO5 347.1731; found
347.1718.
3.1.3. 8-ꢀ20,30-Dihydroxypropyl)-8-phenylmethoxycar-
bonylamino-1,4-dioxaspiro[4.5]decane ꢀ4). To a solution
of 3 ,4.12 g, 12.4 mmol) in acetone ,3.5 ml) and H2O
,7.5 ml) were successively added N-methylmorpholine
N-oxide ,2.05 g, 17.5 mmol) and 0.02 M solution of
osmium tetroxide in tert-BuOH ,3.2 ml, 0.064 mmol). The
mixture was stirred at room temperature for 5 h, then
quenched with saturated aqueous NaHSO3 and extracted
with AcOEt. The extract was dried over MgSO4 and concen-
trated under reduced pressure. The residue was puri®ed by
column chromatography on silica gel eluted with AcOEt to
1
give 4 ,4.28 g, 11.7mmol, 94%) as a colorless oil. H NMR
,CDCl3) d: 1.50±1.81 ,10H, m), 2.09±2.18 ,1H, m), 2.22±
2.35 ,1H, m), 3.39 ,1H, dd, Jˆ10.9, 7.9 Hz), 3.52 ,1H, dd,
Jˆ10.9, 3.6 Hz), 3.82±3.94 ,5H, m), 4.79 ,1H, br s), 5.05 ,s,
2 H), 7.31±7.38 ,m, 5 H). 13C NMR ,CDCl3) d: 30.3 ,t),
30.5 ,t), 32.8 ,t), 33.3 ,t), 41 ,t), 54 ,s), 64.2 ,t), 64.3 ,t), 66
,t), 67,t), 69 ,d), 108 ,s), 128.0 ,t £2), 128.1 ,t), 128.5 ,t£2),
136 ,s), 156 ,s). IR ,CHCl3) cm21: 3400, 1710. EI-MS m/z:
365 ,M1), 101. HR-MS m/z: calcd for C19H27NO6 365.1837;
found 365.1802.
3.1.6. 8-ꢀ20-tert-Butyldimethylsilyloxy-30-tosyloxypropyl)-
8-phenylmethoxycarbonylamino-1,4-dioxaspiro[4.5]de-
cane ꢀ8). To a solution of 5 ,1.59 g, 3.06 mmol) in DMF
,1.5 ml) were successively added imidazole ,417mg,
6.13 mmol) and tert-butyldimethylsilyl chloride ,553 mg,
3.67mmol). The mixture was stirred at room temperature
for 4.5 h, then quenched with saturated aqueous NaCl, and
extracted with AcOEt. The extract was dried over MgSO4
and concentrated under reduced pressure. The residue was
puri®ed by column chromatography on silica gel eluted with
hexane/AcOEt ,3:1) to give 8 ,1.78 g, 2.81 mmol, 92%) as a
colorless oil. 1H NMR ,CDCl3) d: 0.01 ,3H, s), 0.02 ,3H, s),
0.81 ,9H, s), 1.58±1.63 ,6H, m), 1.75 ,1H, dd, Jˆ14.8,
3.1.4. 8-ꢀ20,30-Epoxypropyl)-8-phenylmethoxycarbonyl-
amino-1,4-dioxaspiro[4.5]decane ꢀ6). To a solution of 4
,3.66 g, 10.0 mmol) in pyridine ,22 ml) were successively
added p-toluenesulfonyl chloride ,2.30 g, 12.1 mmol) and

4922
S. Nagumo et al. / Tetrahedron 58 *2002) 4917±4924
5.9 Hz), 2.02 ,1H, dd, Jˆ14.8, 5.1 Hz), 2.06±2.18 ,2H, m),
2.43 ,3H, s), 3.78±4.01 ,7H, m), 4.67 ,1H, br s), 4.99 ,1H, d,
Jˆ11.9 Hz), 5.05 ,1H, d, Jˆ11.9 Hz), 7.25±7.37 ,7H, m),
7.77 ,2H, d, Jˆ8.3 Hz). 13C NMR ,CDCl3) d: 24.6 ,q),
24.3 ,q), 18 ,q), 22 ,q), 26 ,q£3), 30.35 ,t), 30.43 ,t),
32.4 ,t), 32.9 ,t), 42 ,t), 53 ,s), 64.2 ,t), 64.3 ,t), 66 ,t), 68
,d), 74 ,t), 108 ,s), 128.0 ,d£2), 128.1 ,d£2), 128.3 ,d),
128.5 ,d£2), 130 ,d£2), 136 ,s), 145 ,s), 154 ,s). IR
,CHCl3) cm21: 3450, 1720, 1600. EI-MS m/z: 633 ,M1),
405, 229. HR-MS m/z: calcd for C32H47NO8SSi 633.2789;
found 633.2787.
2.22 ,1H, dd, Jˆ13.7, 7.4 Hz), 2.98±3.07 ,2H, m), 3.29 ,1H,
d, 17.0 Hz), 3.93 ,4H, s), 4.41 ,1H, m), 5.45 ,1H, br s), 7.19
1
,1H, br s). IR ,CHCl3) cm21: 1680. EI-MS m/z: 27 0 ,M ),
226. HR-MS m/z: calcd for C13H22N2O4 270.1577; found
270.1567.
3.1.9. Dispiro[1-aminocarbonylmethyl-3-tosyloxypyr-
rolidine-5,10-cyclohexane-40,200-1,3-dioxolane] ꢀ14). To a
solution of 13 ,50.0 mg. 0.185 mmol) in pyridine ,1 ml)
were successively added tosyl chloride ,353 mg,
1.85 mmol)
and
dimethylaminopyridine
,22.6 mg,
0.185 mmol). The reaction mixture was stirred at room
temperature for 4.5 h, and then quenched with saturated
aqueous NaCl and extracted with AcOEt. The extract was
dried over MgSO4 and concentrated under reduced pressure.
The residue was puri®ed by column chromatography on
silica gel eluted with hexane/AcOEt ,1:1) to give 14
3.1.7. Dispiro[1-tert-butoxycarbonyl-3-hydroxypyrroli-
dine-5,10-cyclohexane-40,200-1,3-dioxolane]
ꢀ12).
A
mixture of 8 ,3.00 g, 4.74 mmol), 5% Pd±C ,70 mg) and
MeOH ,30 ml) was stirred under H2 atmosphere for 3 h. The
reaction mixture was ®ltered, and the ®ltrate was concen-
trated under reduced pressure to give crude 9 ,2.40 g). To a
solution of 9 in benzene ,25 ml) was added 1,8-diaza-
bicyclo[5.4.0]undec-7-ene ,2.3 ml, 15.4 mmol). The
mixture was re¯uxed for 3.5 h, then quenched with saturated
aqueous NaHCO3 and extracted with AcOEt. The extract
was washed with saturated aqueous NaCl, dried over
MgSO4 and concentrated under reduced pressure to give
crude 10 ,1.66 g). To a solution of 10 in dioxane ,10 ml)
were successively added triethylamine ,1.3 ml, 9.34 mmol)
and 2-,tert-butoxycarbonyloxyimino)-2-phenylacetonitrile
,2.30 g, 9.35 mmol). The reaction mixture was stirred at
room temperature for 3.5 h, then quenched with saturated
aqueous NaCl and extracted with AcOEt. The extract was
dried over MgSO4 and concentrated under reduced pressure
to give crude 11 ,4.25 g). After rough puri®cation by
column chromatography on silica gel, 11 was dissolved in
THF. To the solution was added 1 M tetrabutylammonium
¯uoride in THF ,4.8 ml, 4.8 mmol). The reaction mixture
was stirred at room temperature for 15 h, then quenched
with saturated aqueous NH4Cl and extracted with AcOEt.
The extract was dried over MgSO4 and concentrated under
reduced pressure. The residue was puri®ed by column chro-
matography on silica gel eluted with AcOEt to give 12
,1.07g, 3.42 mmol, 72% from 8) as a white crystalline
solid, mp 213±2148C ,AcOEt). 1H NMR ,CDCl3) d:
1.22±1.80 ,8H, m), 1.49 ,9H, s), 2.09 ,2H, m), 2.70 ,1H,
br s), 3.40±3.70 ,2H, m), 3.93 ,4H, s), 4.35 ,1H, m). IR
,CHCl3) cm21: 1670. EI-MS m/z: 313 ,M1), 257, 101.
HR-MS m/z: calcd for C16H27NO5 313.1887; found
313.1861.
1
,56.3 mg, 0.133 mmol, 72%) as a colorless oil. H NMR
,CDCl3) d: 1.25±1.62 ,6H, m), 1.64±1.80 ,4H, m), 2.08
,2H, m), 2.46 ,3H, s), 3.04 ,1H, dd, Jˆ10.9, 3.1 Hz), 3.24
,1H, dd, Jˆ10.9, 5.9 Hz), 3.53 ,1H, d, Jˆ17.5 Hz), 3.61
,1H, d, Jˆ17.5 Hz), 3.92 ,4H, s), 5.01 ,1H, m), 7.36 ,2H,
d, Jˆ8.5 Hz), 7.79 ,2H, d, Jˆ8.5 Hz). EI-MS m/z: 406
,M12H2O). HR-MS m/z: calcd for C20H26N2O5S
406.1561; found 406.1594.
3.1.10. Dispiro[1,3-dioxolane-2,10-cyclohexane-40,500-1-
ethoxycarbonylmethyl-3-hydroxypyrrolidine] ꢀ16). Crude
amine 10 ,1.32 g) was prepared from 8 ,2.45 g, 3.87mmol)
according to the already described method. To a solution of
10 in acetonitrile ,20 ml) were successively added potassium
carbonate ,1.61 g, 11.7mmol)) and ethyl bromoacetate
,1.3 ml, 11.8 mmol). The reaction mixture was stirred at
room temperature for 2.5 h, then quenched with saturated
aqueous NaCl, extracted with AcOEt. The extract was
dried over MgSO4 and concentrated under reduced pressure
to give crude product 15 ,1.98 g). To a solution of 15 in THF
,1 ml) was added 1 M tetrabutylammonium ¯uoride in THF
,5.8 ml, 5.80 mmol). The reaction mixture was stirred at
room temperature for 15 h, and then quenched with saturated
aqueous NH4Cl. To the mixture was added potassium sodium
,1)-tartrate tetrahydrate ,Rochelle salt). The mixture was
extracted with AcOEt. The extract was dried over Na2SO4
and concentrated under reduced pressure. The residue was
puri®ed by column chromatography on silica gel eluted
with AcOEt to give 16 ,964 mg, 3.22 mmol, 83% from 8)
as a colorless oil. 1H NMR ,CDCl3) d: 1.27,3H, t,
Jˆ7.1 Hz), 1.52±1.88 ,9H, m), 2.08 ,1H, dd, Jˆ14.0,
6.9 Hz), 2.36 ,1H, br s), 2.94±2.99 ,1H, m), 3.10 ,1H, dd,
Jˆ9.7, 5.0 Hz), 3.27 ,1H, d, Jˆ16.8 Hz), 3.45 ,1H, d,
Jˆ16.8 Hz), 3.93 ,4H, s), 4.16 ,2H, q, Jˆ7.1 Hz), 4.30
,1H, m). 13C NMR ,CDCl3) d 14 ,q), 29 ,t), 31.7,t), 32.2
,t), 32.8 ,t), 44 ,t), 49 ,t), 60 ,t), 61 ,t), 62 ,s), 64.1 ,t), 64.3 ,t),
70 ,d), 108 ,s), 172 ,s). IR ,neat) cm21: 3400, 1730. EI-MS
m/z: 299 ,M1), 256, 198. HR-MS m/z: calcd for C15H25NO5
299.1731; found 299.1761.
3.1.8. Dispiro[1-aminocarbonylmethyl-3-hydroxypyr-
rolidine-5,10-cyclohexane-40,200-1,3-dioxolane] ꢀ13).
A
mixture of 12 ,96.0 mg, 0.307mmol) and tri¯uoroacetic
acid ,0.36 ml) was stirred at 08C for 30 min, and then
concentrated under reduced pressure to give crude amine.
To a solution of the amine crude in acetonitrile ,2 ml) were
successively added potassium carbonate ,129 mg,
0.935 mmol) and iodoacetamide ,86.0 mg, 0.465 mmol).
The mixture was stirred at room temperature, then quenched
with ethanol, ®ltered, and the ®ltrate was concentrated under
reduced pressure. The residue was puri®ed by column
chromatography on silica gel eluted with dichloro-
methane/ethanol/ammonia ,10:1:1) to give 13 ,65.5 mg,
0.243 mmol, 79%) as a white crystalline solid, mp 210±
3.1.11. Dispiro[3-azide-1-ethoxycarbonylmethylpyrroli-
dine-5,10-cyclohexane-40,200-1,3-dioxolane] ꢀ17). To a
solution of 16 ,347mg, 1.16 mmol) in THF ,4 ml) were
successively added triphenylphosphine ,456 mg, 1.74
mmol), diethyl azodicarboxylate ,0.27ml, 1.74 mmol) and
diphenylphosphoryl azide ,0.37ml, 1.74 mmol). The
1
2118C ,AcOEt). H NMR ,CDCl3) d: 1.28±1.84 ,10H, m),

S. Nagumo et al. / Tetrahedron 58 *2002) 4917±4924
4923
reaction mixture was stirred at room temperature for 2 h,
and then concentrated under reduced pressure. The residue
was puri®ed by column chromatography on silica gel eluted
with hexane/AcOEt ,3:1) to give 17 ,308 mg, 0.951 mmol,
solution of 55% sodium hydride ,35 mg, 0.802 mmol) in
THF ,4 ml) were successively added a solution of 19
,142 mg, 0.563 mmol) in THF ,2 ml) and iodomethane
,0.08 ml, 1.3 mmol) at 08C. The reaction mixture was
further stirred at room temperature for 1.5 h, then quenched
with H2O and extracted with CHCl3. The extract was dried
over MgSO4 and concentrated under reduced pressure. The
residue was puri®ed by column chromatography on silica
gel eluted with chloroform/methanol ,30:1), which was
saturated by ammonia, to give 20 ,84.1 mg, 0.316 mmol,
56%) as white crystalline solid, mp 128±1308C ,AcOEt±
1
82%) as a colorless oil. H NMR ,CDCl3) d: 1.26 ,3H, t,
Jˆ7.1 Hz), 1.54±1.79 ,8H, m), 1.90 ,1H, dd, Jˆ13.7,
4.0 Hz), 2.16 ,1H, dd, Jˆ13.7, 8.4 Hz), 2.95 ,1H, dd,
Jˆ10.1, 4.5 Hz), 3.27±3.40 ,3H, m), 3.93 ,4H, s), 4.03
,1H, m), 4.16 ,2H, q, Jˆ7.1 Hz). 13C NMR ,CDCl3) d: 14
,q), 29.5 ,t), 30.2 ,t), 33 ,t£2), 40 ,t), 49 ,t), 57,t), 58 ,d), 61
,t), 63 ,s), 64.2 ,t), 64.3 ,t), 108 ,s), 171 ,s). IR ,neat) cm21
:
2100, 1740. EI-MS m/z: 324 ,M1), 251, 101. HR-MS m/z:
hexane). H NMR ,CDCl3) d: 1.49±1.93 ,10H, m), 2.90
1
calcd for C15H24N4O4 324.1769; found 324.1777.
,3H, s), 3.05 ,1H, d, Jˆ12.2 Hz), 3.24 ,1H, dd, Jˆ12.2,
2.6 Hz), 3.48 ,1H, d, Jˆ18.8 Hz), 3.59 ,1H, d,
Jˆ18.8 Hz), 3.60±3.63 ,1H, m), 3.94 ,4H, s). 13C NMR
,CDCl3) d: 31.8 ,t), 32.5 ,t), 32.7,t), 33.3 ,q), 36 ,t), 45
,t), 55 ,t), 56 ,t), 60 ,d), 64.1 ,s), 64.20 ,t), 64.24 ,t), 108 ,s),
168 ,s). IR ,CHCl3) cm21: 1630. EI-MS m/z: 266 ,M1), 235,
113. HR-MS m/z: calcd for C14H22N2O3 266.1629; found
266.1634. Anal. calcd for C14H22N2O3: C 63.14, H 8.33, N
10.52. Found: C 63.39, H 8.38, N 10.45.
3.1.12.
rolidine-5,10-cyclohexane-40,200-1,3-dioxolane] ꢀ18).
Dispiro[3-amino-1-ethoxycarbonylmethylpyr-
A
mixture of 17 ,166 mg, 0.512 mmol), 5% Pd±C ,trace
amount) and MeOH ,2 ml) was stirred under H2 atmosphere
for 1.5 h. The reaction mixture was ®ltered, and the ®ltrate
was concentrated under reduced pressure. The residue was
puri®ed by column chromatography on silica gel eluted with
chloroform which was saturated by ammonia/methanol
,9:1) to give 18 ,114 mg, 0.383 mmol, 75%) as a colorless
oil. 1H NMR ,CDCl3) d: 1.26 ,3H, t, Jˆ7.1 Hz), 1.31±1.79
,11H, m), 2.23 ,1H, dd, Jˆ13.2, 8.2 Hz), 2.76 ,1H, dd,
Jˆ9.1, 4.6 Hz), 3.09 ,1H, dd, Jˆ9.1, 6.6 Hz), 3.23 ,1H, d,
Jˆ16.7Hz), 3.40 ,1H, d, Jˆ16.7Hz), 3.45±3.54 ,1H, m),
3.93 ,4H, m), 4.16 ,2H, q, Jˆ7.1 Hz). 13C NMR ,CDCl3) d:
14 ,q), 29 ,t), 31.7,t), 32.4 ,t), 32.6 ,t), 45 ,t), 49.0 ,d), 49.5
,t), 60.4 ,t), 60.9 ,t), 63 ,s), 64.1 ,t), 64.2 ,t), 108 ,s), 172 ,s).
IR ,neat) cm21: 3350, 1740. EI-MS m/z: 298 ,M1), 225,
197. HR-MS m/z: calcd for C15H26N2O4 298.1891; found
298.1917.
3.1.15. Aldol reaction of 20with 22. To a solution of 20
,102 mg, 0.383 mmol) in THF ,5 ml) was added dropwise
0.2 M solution of lithium diisopropylamide in THF ,3.8 ml,
0.760 mmol). After being further stirred at 2788C for
20 min, a solution of 22 ,144 mg, 0.758 mmol) in THF
,2 ml) was added dropwise to the reaction mixture. After
being further stirred at 2788C for 20 min, the mixture was
quenched with saturated aqueous NaCl and extracted with
CHCl3. The extract was dried over MgSO4 and concentrated
under reduced pressure. The residue was puri®ed by column
chromatography on ¯orisil eluted with hexane/AcOEt ,3:1)
to give 23A ,less polar, 62.9 mg, 0.138 mmol, 36%) and
23B ,more polar, 85.7mg, 0.188 mmol, 49%).
3.1.13. Dispiro[1,4-diazabicyclo[3.2.1]octan-3-one-7,10-
cyclohexane-40,200-1,3-dioxolane] ꢀ19). To a solution of
18 ,552 mg, 1.85 mmol) in H2O ,7ml) was added lithium
hydroxide ,66.7mg, 2.78 mmol). The reaction mixture was
stirred at room temperature for 40 min, and then concen-
trated under reduced pressure to give crude amino acid
,625 mg). To a solution of the crude in dimethylformamide
,40 ml) was added triethylamine ,0.77 ml, 5.55 mmol).
After being stirred for 10 min, diphenylphosphoryl azide
,1.2 ml, 5.55 mmol) was added and the resulting reaction
mixture was further stirred at room temperature for 1.5 h,
and then concentrated under reduced pressure. The residue
was puri®ed by column chromatography on silica gel eluted
with chloroform/methanol ,30:1), which was saturated by
ammonia, to give 19 ,234 mg, 0.929 mmol, 50%) as a white
1
23A: Mp 149±1508C ,AcOEt±hexane). H NMR ,CDCl3)
d: 1.23±1.86 ,10H, m), 1.74 ,3H, s), 1.79 ,3H, s), 2.77 ,1H,
d, Jˆ12.7Hz), 2.93 ,3H, s), 3.13 ,1H, d, Jˆ12.7Hz), 3.42
,1H, d, Jˆ8.1 Hz), 3.56 ,1H, m), 3.83 ,4H, s), 4.51 ,2H, d,
Jˆ6.6 Hz), 4.96 ,1H, d, Jˆ8.1 Hz), 5.24 ,1H, br s, OH),
5.51 ,1H, m), 6.88 ,2H, d, Jˆ8.8 Hz), 7.32 ,2H, d,
Jˆ8.8 Hz). 13C NMR ,CDCl3) d 18 ,q), 26 ,q), 31.5 ,t),
31.8 ,t), 32.3 ,t), 33.5 ,q), 36.0 ,t), 47,t), 52 ,t), 60 ,d),
64.0 ,t), 64.1 ,t), 64.4 ,s), 64.9 ,t), 66 ,d), 74 ,d), 108 ,s),
114.1 ,d), 114.3 ,d), 120 ,d), 128 ,d£2), 134 ,s), 138 ,s), 158
,s), 170 ,s). IR ,CHCl3) cm21: 3300, 1610. EI-MS m/z: 457
,M111), 266. HR-MS m/z: calcd for C26H36N2O51H
457.2622; found 457.2691. Anal. calcd for C26H36N2O5: C
68.40, H 7.95, N 6.14. Found: C 68.38, H 8.14, N 6.06.
1
crystalline solid, mp 182±183.58C ,AcOEt±benzene). H
NMR ,CDCl3) d: 1.53±1.96 ,10H, m), 3.05 ,1H, d,
Jˆ12.2 Hz), 3.18 ,1H, dd, Jˆ12.2, 2.5 Hz), 3.51 ,1H, d,
Jˆ18.8 Hz), 3.61 ,1H, d, Jˆ18.8 Hz), 3.79 ,1H, br s),
3.95 ,4H, s), 7.12 ,1H, br s). 13C NMR ,CDCl3) d: 31.8
,t), 32.6 ,t), 32.8 ,t), 36 ,t), 48 ,t), 53 ,d), 55 ,t), 56 ,t),
64.1 ,s), 64.22 ,t), 64.26 ,t), 108 ,s), 171 ,s). IR
,CHCl3) cm21: 3250, 1660. EI-MS m/z: 252 ,M1), 166,
83. HR-MS m/z: calcd for C13H20N2O3 252.1473; found
252.1472. Anal. calcd for C13H20N2O3: C 61.88, H 7.99, N
11.10. Found: C 62.07, H 8.08, N 11.14.
1
23B: Mp 152±1538C ,AcOEt±hexane). H NMR ,CDCl3)
d: 1.50±1.94 ,10H, m), 1.73 ,3H, s), 1.79 ,3H, s), 2.84 ,1H,
d, Jˆ12.5 Hz), 2.86 ,3H, s), 3.28 ,1H, dd, Jˆ12.5, 1.7Hz),
3.57±3.60 ,2H, m), 3.94 ,4H, s), 4.49 ,2H, d, Jˆ6.6 Hz),
4.76 ,1H, d, Jˆ7.6 Hz), 4.97 ,1H, br s), 5.50 ,1H, m), 6.89
,2H, d, Jˆ8.6 Hz), 7.29 ,2H, d, Jˆ8.6 Hz). 13C NMR
,CDCl3) d: 18 ,q), 26 ,q), 32.1 ,t), 32.39 ,t), 32.42 ,t),
33.4 ,q), 36.0 ,t), 45 ,t), 52 ,t), 60 ,d), 64.26 ,t), 64.34 ,t),
64.45 ,s), 64.7,t), 66 ,d), 74 ,d), 108 ,s), 114 ,d £2), 120 ,d),
129 ,d£2), 134 ,s), 138 ,s), 159 ,s), 168 ,s). IR
,CHCl3) cm21
: 3350, 1640, 1610. EI-MS m/z: 457
3.1.14. Dispiro[1,3-dioxolane-2,10-cyclohexane-40,700-4-
methyl-1,4-diazabicyclo[3.2.1]octan-3-one] ꢀ20). To a
,M111), 266. HR-MS m/z: calcd for C26H36N2O51H

4924
S. Nagumo et al. / Tetrahedron 58 *2002) 4917±4924
457.2622; found 457.2720. Anal. calcd for C26H36N2O5: C
68.40, H 7.95, N 6.14. Found: C 68.15, H 8.10, N 6.04.
HCl ,0.1 ml). The whole was further stirred at room
temperature for 2 h, and then quenched with saturated
aqueous NaHCO3 and extracted with CHCl3. The extract
was dried over Na2SO4 and concentrated under reduced
pressure. The residue was puri®ed by column chromato-
graphy on silica gel eluted with chloroform/methanol
,30:1), which was saturated by ammonia, to give
TAN1251A ,3.6 mg, 9.47 mmol, 40% from 24) as a pale
3.1.16. Dehydration of 23A and 23B. To a solution of 23A
,17.9 mg, 39.3 mmol) in dichloromethane ,1 ml) were
successively added triethylamine ,0.055 ml, 0.392 mmol)
and methanesulfonyl chloride ,0.018 ml, 0.233 mmol) at
2788C. After being further stirred at 08C for 1 h, the reac-
tion was quenched with saturated aqueous NaCl and
extracted with CHCl3. The extract was dried over MgSO4
and concentrated under reduced pressure. To a solution of
the crude ,43.6 mg) compound in THF ,1 ml) was added
potassium tert-butoxide ,26 mg, 0.232 mmol) at 08C.
After being further stirred at 08C for 1 h, the mixture was
quenched with saturated aqueous NaCl and extracted with
CHCl3. The extract was dried over MgSO4 and concentrated
under reduced pressure. Recrystallization of the residue
from AcOEt±hexane gave 24 ,14.1 mg, 32.2 mmol, 82%)
as white crystalline solid.
1
yellow oil. H NMR ,CDCl3) d: 1.48 ,1H, dd, Jˆ13.9,
5.6 Hz), 3.29 ,1H, dd), 1.74 ,3H, s), 1.79 ,3H, s), 1.83±
2.19 ,8H, m), 2.19 ,3H, s), 2.77 ,1H, m), 2.92±3.04 ,2H,
m), 3.25±3.34 ,3H, m), 4.47,2H, d, Jˆ6.8 Hz), 5.49 ,1H,
m), 6.02 ,1H, br s), 6.80 ,2H, d, Jˆ8.8 Hz), 7.76 ,2H, d,
Jˆ8.8 Hz). 13C NMR ,CDCl3) d: 18.17,q), 25.79 ,q), 32.18
,t), 34.48 ,t), 38.20 ,t), 38.54 ,t), 38.61 ,t), 42.51 ,q), 55.72
,t), 58.53 ,t), 61.15 ,d), 64.01 ,s), 64.62 ,t), 114.03 ,d£2),
119.65 ,d), 122.82 ,d), 128.53 ,s), 130.69 ,d£2), 138.12 ,s),
141.59 ,s), 157.83 ,s), 211.97 ,s). IR ,CHCl3) cm21: 1700,
1600. EI-MS m/z: 380 ,M1), 270, 201. HR-MS m/z: calcd
for C24H32N2O2 380.2462; found 380.2457. These spectro-
scopic data were identical with those of the natural product.
To a solution of 23B ,20.6 mg, 45.2 mmol) in dichloro-
methane ,1 ml) were successively added triethylamine
,0.066 ml, 0.477 mmol) and methanesulfonyl chloride
,0.02 ml, 0.259 mmol) at 2788C. After being further stirred
at 08C for 3 h, the reaction was quenched with saturated
aqueous NaCl and extracted with CHCl3. The extract was
dried over MgSO4 and concentrated under reduced pressure.
To a solution of the residue ,27mg) in THF ,1 ml) was
added potassium tert-butoxide ,30 mg, 0.268 mmol) at
08C. After being further stirred at 08C for 30 min, the
mixture was quenched with saturated aqueous NaCl and
extracted with CHCl3. The extract was dried over MgSO4
and concentrated under reduced pressure. Recrystallization
of the residue from AcOEt±hexane gave 24 ,12.6 mg,
28.8 mmol, 64%) as white crystalline solid.
Acknowledgements
We thank Discovery Research Laboratories, Takeda
Chemical Industries Ltd., for providing us a sample of
TAN1251A.
References
1. Shirafuji, H.; Tubotani, S.; Ishimaru, T.; Harada, S. PCT Int.
Appl. 1991, WO 91 13, 887; Chem. Abstr. 1992, 116, 39780t.
2. A part of this work has been already reported: Nagumo, S.;
Nishida, A.; Yamazaki, C.; Murashige, K.; Kawahara, N.
Tetrahedron Lett. 1998, 39, 4493.
Mp 217±2198C ,AcOEt±hexane). 1H NMR ,CDCl3) d:
1.40±2.07,10H, m), 1.75 ,3H, s), 1.80 ,3H, s), 3.01 ,3H,
s), 3.12 ,1H, dd, Jˆ12.2, 2.2 Hz), 3.29 ,1H, dd, Jˆ12.2,
2.0 Hz), 3.72 ,1H, m), 3.77±3.89 ,4H, m), 4.54 ,2H, d,
Jˆ6.6 Hz), 5.50 ,1H, m), 6.90 ,2H, d, Jˆ9.0 Hz), 7.36
,1H, s), 8.08 ,2H, d, Jˆ9.0 Hz). 13C NMR ,CDCl3) d: 18
,q), 26 ,q), 30 ,t), 32.0 ,t), 32.4 ,t), 32.6 ,t), 34 ,q), 36 ,t), 58
,t), 61 ,d), 64.2 ,t), 64.3 ,t), 64.7,t), 66 ,s), 74 ,d), 108 ,s),
114 ,d£2), 120 ,d), 128 ,s), 129 ,d), 133 ,d£2), 137.6 ,s),
138.2 ,s), 159 ,s), 163 ,s). IR ,CHCl3) cm21: 1650, 1600.
EI-MS m/z: 438 ,M1), 370, 216. HR-MS m/z: calcd for
C26H34N2O4 438.2517; found 438.2487. Anal. calcd for
C26H34N2O4: C 71.21, H 7.81, N 6.39. Found: C 71.23, H
7.98, N 6.34.
3. After publication of our preliminary communication, three
syntheses of ,2)-TAN1251A have been achieved Snider,
B. B.; Lin, H. Org. Lett. 2000, 2, 643. Wardrop, D. J.;
Basak, A. Org. Lett. 2001, 3, 1053. Mizutani, H.; Takayama,
J.; Soeda, Y.; Honda, T. Tetrahedron Lett. 2002, 43, 2411.
4. Miller, R. D.; Goelitz, P. J. Org. Chem. 1981, 46, 1616.
5. Nitz, T. J.; Volkots, D. L.; Aldous, D. J.; Oglesby, C. O.
J. Org. Chem. 1994, 59, 5828.
6. Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203.
7. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
8. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 1977.
9. Qian, L.; Sun, Z.; Deffo, T.; Mertes, K. B. Tetrahedron Lett.
1990, 31, 6469.
3.1.17. Preparation of TAN1251A. To a mixture of lithium
aluminium hydride ,10.0 mg, 263 mmol) and Et2O ,0.5 ml)
was added aluminium chloride ,12.0 mg, 89.9 mmol) and
resulting mixture was further stirred at 08C for 10 min. To
the reaction mixture was added a solution of 24 ,10.4 mg,
23.7 mmol) in Et2O ,0.5 ml). After being stirred at room
temperature for 1 h, the reaction mixture was quenched
with saturated aqueous NaHCO3 and extracted with
CHCl3. The extract was dried over MgSO4 and concentrated
under reduced pressure to give crude 25 ,5.2 mg). To a
solution of the crude 25 in acetone ,0.3 ml) was added 1N
10. Chari, V. M.; Aurnhammer, G.; Wagner, H. Tetrahedron Lett.
1970, 3079.
11. Semi-empirical calculations were carried out by the MOPAC
2002 computer package.
12. The structure of double bond for 24 was identi®ed based on its
successful conversion into TAN1251A.
13. Tsuda, Y.; Nakai, A.; Ito, K.; Suzuki, F.; Haruma, M.
Heterocycles 1984, 22, 1817.