Facile synthesis of enantiopure (-)-TAN1251A

Article abstract of DOI:10.1016/S0040-4039(02)00296-4

Formal total synthesis of enantiopure (-)-TAN1251A, a muscarinic M₁ receptor antagonist, was achieved via a spirocyclic carbon-nitrogen bond formation by the use of aromatic oxidation with bis(acetoxy)iodobenzene as a key step.

Full text of DOI:10.1016/S0040-4039(02)00296-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2411–2414
Facile synthesis of enantiopure (−)-TAN1251A
Hirotake Mizutani, Jun Takayama, Yukio Soeda and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
Received 19 January 2002; revised 8 February 2002; accepted 12 February 2002
Abstract—Formal total synthesis of enantiopure (−)-TAN1251A, a muscarinic M1 receptor antagonist, was achieved via a
spirocyclic carbonꢀnitrogen bond formation by the use of aromatic oxidation with bis(acetoxy)iodobenzene as a key step. © 2002
Elsevier Science Ltd. All rights reserved.
TAN1251A 1 and B 2, isolated from a culture of
Penicillium thomii RA-89 by Takeda Industries, are a
naturally occurring novel type of alkaloid, which con-
tain unique structural features with a 1,4-diazabicy-
respectively. We thought that a straightforward method
for obtaining the key spirocyclic ring system would be
the carbonꢀnitrogen bond formation of a secondary
amine,6 via aromatic oxidation with a hypervalent
iodine reagent,7 or via an aminylium ion intermediate,
generated from the corresponding N-halogeno-
compound.8
clo[3.2.1]octane ring system and
a
spirocyclic
cyclohexanone (Fig. 1).1
These alkaloids exhibit cholinergic activity and inhibit
the acetylcholine-induced contraction of guinea pig
ileum with ED50 values of 8.0 and 10.0 nM, respec-
tively.2 TAN1251A is also known as a selective mus-
carinic M1 subtype receptor antagonist.2 Due to their
attractive biological properties and structural novelty,
the TAN1251 series of compounds have been the sub-
ject of extensive synthetic efforts which have culmi-
nated in several total syntheses involving one racemic3
and two chiral syntheses,4,5 in recent years. In the latter
chiral syntheses, the problematic spirocyclic car-
bonꢀnitrogen bond was constructed by employing a
1,3-dipolar cycloaddition of the chiral nitron derived
from tyrosine leading to the determination of their
absolute configuration,4 and by using an N-
acylnitrenium ion intermediate as a reactive species,5
Based on our retrosynthetic scheme,
L-tyrosine was
chosen as the starting material with its chirality being
transferred into the chiral center of TAN1251A. More-
over, the requisite secondary amine for aromatic oxida-
tion will readily be obtained by condensation of a
tyrosine derivative with glycine, as shown in Scheme 1.
Thus, a readily accessible tyrosine methyl ester hydro-
chloride 3 was converted into the carbamate 4 by
treatment with ethyl chlorocarbonate in water in the
presence of potassium carbonate, in 88% yield. After
benzylation of 4 in the usual manner, the resulting
benzyl ether 5 was subjected to lithium aluminum
hydride reduction to give the alcohol 6. The amino
group of 6 was then protected as its Boc derivative 7.
Dess–Martin oxidation of 7 gave the aldehyde 8, which
was further condensed with glycine methyl ester in the
presence of sodium cyanoborohydride9 to provide the
amine 9. Deprotection of the Boc group of 9 gave the
secondary amine 10, which was treated with 25%
ammonium hydroxide in ethanol to furnish the cyclized
compound 11, successfully (Scheme 2).
NMe
N
O
R
O
1 TAN1251A (R = H)
2 TAN1251B (R = OH)
First, we attempted a carbonꢀnitrogen bond formation
at this stage via an aminylium ion intermediate by
chlorination of 11 with NCS, followed by treatment
with silver oxide.8 However, none of the desired
product could be isolated. This bond formation was not
effective for the formation of the desired product even
Figure 1.
* Corresponding author. Tel.: +81-3-5498-5791; fax: +81-3-3787-0036;
e-mail: honda@hoshi.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00296-4

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H. Mizutani et al. / Tetrahedron Letters 43 (2002) 2411–2414
Scheme 1. Retrosynthetic route for TAN1251A.
to the ketone 14 by treatment with 2 equiv. 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 the partial
reduction product 15 in 42% yield. The enone 15 could
also be converted to the ketone 14 by further reduction
under the same reduction conditions as above in 80%
yield. When the reduction of 13 was carried out with 3
equiv. of Et3SiH under similar reaction conditions at
0°C for 36 h, the ketone 14 was isolated in 60% yield
together with the enone 15 in 9% yield (Scheme 4).
The structure of the enone 15 was determined based on
the NMR study, where NOEs were observed between
the methylene proton and the olefinic proton, as
depicted in Fig. 2. Finally, ketalization of 14 with
ethylene glycol in refluxing benzene in the presence of
pyridinium p-toluenesufonate afforded the known key
intermediate 16 for the synthesis of (−)-TAN1251A.
The spectroscopic data of 16 including its optical rota-
tion {[h]D +15.6 (c=0.71, CHCl3); lit.,5 [h]D +15.2
(CHCl3)} were identical with those reported.5 Since this
compound 16 has already been transformed into (−)-
TAN1251A by Wardrop and co-worker,5 this synthesis
constitutes its formal total synthesis.
Scheme 2. (a) ClCO2Et, K2CO3, H2O, rt (88%); (b) BnBr,
K2CO3, DMF, rt (88%); (c) LiAlH4, THF, reflux, (92%); (d)
(Boc)2O, rt (92%); (e) Dess–Martin oxid. (86%); (f) glycine
methyl ester, NaB(CN)H3, MeOH, rt (87%); (g): CF3CO2H,
CH2Cl2, rt (96%); (h) 25% NH4OH, EtOH, rt (92%); (I)
Pd–C, H2, rt (96%).
In summary, we have disclosed a facile formal synthesis
of optically pure (−)-TAN1251A, in which aromatic
oxidation of the secondary amine with bis(ace-
toxy)iodobenzene was employed as the key reaction.
The synthetic strategy developed here would be applica-
ble to the synthesis of other TAN series of compounds.
with the use of a phenolic compound 12, derived from
11 by debenzylation under catalytic hydrogenation over
palladium on carbon. On the other hand, the aromatic
oxidation of 12 with bis(acetoxy)iodobenzene in 2,2,2-
trifluoroethanol afforded the desired spiro compound
1310 in 43% yield. When this oxidation was carried out
in hexafluoroisopropanol as the solvent, the yield was
increased to 69%. (Scheme 3) Since the basic skeleton
of the target compound was thus constructed in rela-
tively short steps, our attention was focused on reduc-
tion of the two carbonꢀcarbon double bonds of the
dienone 13.
O
O
O
NMe
NMe
NMe
NCS
HN
Cl
N
then Ag2O
N
R=Bn or H
RO
RO
O
11 or 12
13
R = H
Although difficulties were initially encountered in
obtaining the desired products by catalytic reduction
under the various reaction conditions attempted, we
found fortunately that the dienone could be converted
PhI(OAc)2, (CF3)2CHOH, 0ºC, 30 min.
Scheme 3. Construction of the spiro-ring system.

H. Mizutani et al. / Tetrahedron Letters 43 (2002) 2411–2414
O
2413
O
O
NMe
NMe
NMe
N
N
N
a
O
O
O
13
14
15
a
O
NMe
NMe
N
N
Ref.
b
O
O
O
O
TAN1251A
16
Scheme 4. (a) Et3SiH (3 equiv.), CuCl, dppf, CH2Cl2, 0°C, (60% for 14; 9% for 15); (b) HO(CH2)2OH, PPTS, benzene, reflux
(66%).
7. For reviews, see: (a) Ochiai, M. Rev. Heteroatom Chem.
H
NMe
1989, 2, 92–111; (b) Moriarty, R. M. Synthesis 1990,
431–447; (c) Moriarty, R. M.; Vaid, R. K.; Koser, G. F.
H
N
H
O
H
H
Synlett 1990, 365–383; (d) Varvoglis, A. The Organic
Chemistry of Polycoordinated Iodine, VCH Publishers
Inc.: New York, 1992; (e) Kita, Y.; Tohma, H.; Yakura,
T. Trends Org. Chem. 1992, 3, 113–128; (f) Stang, P. J.;
Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178; (g)
Varvogolis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: San Diego, 1997; (h) Kitamura, T.;
Fujiwara, Y. Org. Prep. Proc. Int. 1997, 29, 409–458.
8. (a) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22,
337–350; (b) Honda, T.; Yamamoto, A.; Cui, Y.; Tsub-
uki, M. J. Chem. Soc., Perkin Trans. 1 1992, 531–532.
9. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am.
Chem. Soc. 1971, 93, 2897–2904.
O
H
Figure 2. Observed NOEs are indicated by arrows for the
enone 15.
Acknowledgements
This work was supported in part by grant from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan.
10. Selected data for 13: Mp 125–126°C. [h]2D0=−23.5 (c=
0.53, CHCl3); 1H NMR (CDCl3) l 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, J=13.8, 4.1 Hz, 1H); 13C
NMR (CDCl3) l 184.8, 166.8, 149.9, 146.6, 129.3, 124.9,
63.4, 60.7, 58.1, 57.2, 45.1, 33.6; IR (KBr) 2970, 1668,
1630, 1488, 1432, 1405, 1318, 1262, 1213, 1100, 1005, 988,
969, 854 cm−1; HRMS m/z found 218.1069 (calcd for
C12H14N2O2, 218.1055). For 14: Mp 92–93°C. [h]2D2=+8.7
(c=0.90, CHCl3); 1H NMR (CDCl3) l 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, 1H), 2.52–2.18 (m, 3H), 2.17–1.93
(m, 4H), 1.88–1.55 (m, 2H); 13C NMR (CDCl3) l 210.1,
167.5, 63.6, 59.7, 56.4, 55.1, 45.3, 38.6, 38.5, 38.1, 34.5,
33.2; IR (KBr) 2955, 2912, 2865, 1715, 1646, 1488, 1425,
1324, 1240, 1212, 1122, 1004, 958, 916 cm−1; anal. calcd
for C12H18N2O2: C, 64.84; H, 8.16; N, 12.60. Found: C,
64.92; H, 8.20; N, 12.51%. For 15: Mp 99–100°C. [h]2D0=
+96.0 (c=0.38, CHCl3); 1H NMR (CDCl3) l 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
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H. Mizutani et al. / Tetrahedron Letters 43 (2002) 2411–2414
J=18.6 Hz, 1H), 3.18 (dd, J=12.2, 2.6 Hz, 1H), 2.98 (d,
(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) l 198.9, 167.2,
150.9, 130.9, 63.4, 61.0, 57.1, 56.6, 48.3, 36.1, 35.4, 33.4;
IR (KBr) 2960, 2862, 1678, 1646, 1485, 1443, 1398, 1323,
1236, 1157, 1052, 1000, 978, 965, 894 cm−1; HRMS m/z
found 220.1204 (calcd for C12H16N2O2, 220.1212). For 16:
J=12.2 Hz, 1H), 2.83 (s, 3H), 1.86–1.62 (m, 7H), 1.60–1.42
(m, 3H); 13C NMR (CDCl3) l 168.2, 107.9, 64.2, 64.2, 64.1,
59.9, 56.3, 55.0, 45.0, 36.4, 33.3, 32.7, 32.5, 31.8; IR (thin
film) 2950, 2930, 2890, 1644, 1488, 1439, 1398, 1320, 1285,
1212, 1154, 1075, 1008, 954, 922, 900 cm−1; HRMS m/z
found 266.1623 (calcd for C14H22N2O3, 266.1630).
11. We used the following asymmetric reduction conditions
with slight modifications: Moritani, Y.; Appella, D. H.;
Jurkauska, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 6797–6798.
1
A colorless oil. [h]D20=+15.6 (c=0.71, CHCl3); H NMR
(CDCl3) l 3.88 (br s, 4H), 3.55–3.49 (m, 2H), 3.41 (d,