Enantiospecific total synthesis of TAN1251C and TAN1251D

Article abstract of DOI:10.1055/s-2004-836065

An enantiospecific total synthesis of TAN1251C and TAN125ID has been achieved. An aromatic oxidation reaction of a secondary amine, which is prepared from two molecules of L-tyrosine derivatives, with hypervalent iodine reagent gave a spirocyclic product

Full text of DOI:10.1055/s-2004-836065

328
LETTER
Enantiospecific Total Synthesis of TAN1251C and TAN1251D
Enantiospecific
T
o
i
tal
S
yn
r
thesis of
o
T
AN1251C
t
and
T
A
a
N1251D ke Mizutani, Jun Takayama, Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
Fax +81(3)54985791; E-mail: honda@hoshi.ac.jp
Received 30 September 2004
constructed by a 1,3-dipolar cycloaddition reaction of the
chiral nitrone derived from L-tyrosine, and also by an
aromatic oxidation of the oxazoline derivative, as a key
step, in each synthesis. Although an aromatic oxidation
Abstract: An enantiospecific total synthesis of TAN1251C and
TAN1251D has been achieved. An aromatic oxidation reaction of a
secondary amine, which is prepared from two molecules of L-ty-
rosine derivatives, with hypervalent iodine reagent gave a spiro-
cyclic product as a key intermediate for the synthesis of TAN1251C with hypervalent iodine reagent was widely utilized to
and D.
construct a carbon-nitrogen bond of the target com-
pounds,6 rare example of its application to a secondary
Key words: TAN1251 alkaloid, total synthesis, aromatic oxida-
tions, hypervalent iodine, spiro cyclization
amine has been reported. Recently, we have succeeded in
the chiral synthesis of TAN1251A starting from L-ty-
rosine and glycine, where the aromatic oxidation of the
secondary amine with hypervalent iodine reagent was
successfully employed, as the key reaction, to construct
the desired spirocyclic carbon-nitrogen bond.7 In this syn-
thesis, however, the benzylidene side chain at the a-posi-
tion of piperazinone ring was introduced at the later stage
of its synthesis. Thus, we investigated to develop more
effective synthetic path to those alkaloids, especially to
TAN1251C and TAN1251D.
TAN1251A (1), B (2), C (3) and D (4), isolated from a
Penicillium thomii RA-89 by researchers at Takeda
Chemical Industries Ltd.,1 have unique structural features
with a 1,4-diazabicyclo[3.2.1]octane ring system and a
spirocyclic cyclohexanone. TAN1251A and B exhibit
cholinergic activity and inhibit the acetylcholine-induced
contraction of Guinea-pig ileum. TAN1251A is also
known as a selective muscarinic M1 subtype receptor an-
tagonist (Figure 1).2
In searching the structures of 3 and 4 for retrosynthetic
disconnections, we focused our attention on the formation
of the spirocyclic carbon-nitrogen bond by an aromatic
oxidation of the dimeric L-tyrosine derivative having a
desired benzyl side chain in its molecule, as depicted in
Scheme 1.
Me
Me
N
N
Me
O
R
O
1: TAN1251A (R = H)
2: TAN1251B (R = OH)
O
Me
N
3: TAN1251C
4: TAN1251D
Me
Me
N
N
N
BnO
N
N
RO
RO
O
Aromatic
Oxidation
O
O
4: TAN1251D (R = Prenyl)
O
3: TAN1251C (R = Prenyl)
Me
N
Figure 1 Family of TAN1251 alkaloid
HN
BnO
L-Tyrosine x 2
Due to the attractive biological activity and also intriguing
structural feature, a number of total synthesis of
TAN1251A have been published to date.3,4 However,
little attention was focused on the chiral synthesis of
TAN1251C and TAN1251D compared to the synthesis of
TAN1251A, and two total syntheses have so far been
reported by Snider4 and Ciufolini,5 respectively, in which
the problematic spirocyclic carbon-nitrogen bond was
HO
Scheme 1 Retrosynthetic route for TAN1251C and TAN1251D
Thus, the requisite starting material was prepared as fol-
lows. The carbamate 57 was converted into its MPM ether
6, in a usual manner, which, on reduction with lithium
aluminum hydride afforded the primary alcohol 7 in 79%
yield from 5. Reaction of 7 with (Boc)2O, followed by
Swern oxidation of the resulting N-Boc derivative 8 gave
the corresponding aldehyde 9 in quantitative yield. The
desired dimeric tyrosine derivative 10 was synthesized by
SYNLETT 2005, No. 2, pp 0328–0330
0
1.
0
2.
2
0
0
5
Advanced online publication: 10.12.2004
DOI: 10.1055/s-2004-836065; Art ID: U27104ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantiospecific Total Synthesis of TAN1251C and TAN1251D
329
condensation of the aldehyde with O-benzyl-L-tyrosine 18, which, on reduction with lithium aluminum hydride
under the reductive amination conditions in the presence afforded the amine 19. Finally, deprotection of the ketal
of sodium cyanoborohydride8 in 90% yield. After selec- group under the acidic conditions furnished
tive deprotection of the N-Boc group with zinc bromide, TAN1251D,13 whose spectroscopic data including specif-
the resulting amine 11 was cyclized with sodium methox- ic optical rotation {[a]D +24.7 (c 0.20, MeOH); lit.,1 [a]D
ide to provide the piperazinone derivative 12, which, on +24 (c 0.47, MeOH); lit.,4 [a]D +22 (c 0.10, MeOH)} were
further treatment with trifluoroacetic acid gave the key identical with those reported. Thus, we were able to estab-
precursor 13 for an aromatic oxidation in 58% yield from lish the facile synthesis of TAN1251D by using an aro-
10 (Scheme 2).
matic oxidation of the secondary amine as the key
reaction (Scheme 3).
OR
O
ii
Me
N
L-Tyrosine
i
ii
EtO2C
i
13
N
N
H
CO2Me
BnO
O
5 R = H
6 R = MPM
O
iv
14
OMPM
OMPM
O
Me
Me
iv
N
N
N
Me
OH
7 R = H
Me
N
RO
N
R
N
CHO
BnO
Boc
O
9
iii
8 R = Boc
R
O
OMPM
15 R = O
16 R = OCH2CH2O
17 R = H
18 R = Prenyl
iii
v
v
vii
H
N
Me
Me
N
N
R
N
vi
O
vii
CO2Me
OBn
TAN1251D
O
10 R = Boc
11 R = H
vi
O
19
OBn
NH
Scheme 3 Reagents and conditions: (i) PhI(OAc)2, (CF3)2CHOH,
0 °C (49%); (ii) CuCl, dppf, Et3SiH, t-BuONa, CH2Cl2, 0 °C (65%);
(iii) ethylene glycol, PPTS, benzene, reflux (99%); (iv) H2, Pd(OH)2,
EtOH, r.t. (99%); (v) prenyl bromide, NaH, THF, 0 °C (73%); (vi)
LAH, AlCl3, Et2O, 0 °C (83%); (vii) 1 M HCl aq, acetone, r.t. (67%).
N
RO
Me
O
12 R = MPM
13 R = H
viii
Scheme 2 Reagents and conditions: (i) MPMCl, K2CO3, DMF, r.t.
(96%); (ii) LAH, THF, reflux (82%); (iii) (Boc)2O, K2CO3, THF–H2O
(1:1), 0 °C (99%); (iv) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C
(99%); (v) O-benzyl-L-tyrosine methyl ester, NaBH3CN, DMF, 0 °C
(90%); (vi) ZnBr2, CH2Cl2, 0 °C (99%); (vii) MeONa, THF, 0 °C
(85%); (viii) CF3CO2H, CH2Cl2, 0 °C (92%).
To accomplish the synthesis of TAN1251C, introduction
of the double bond in the piperazine ring would be re-
quired. Fortunately, we could find that DIBALH reduc-
tion of the amide in Et2O provided the desired enamine 20,
in 70% yield, in one step. At this reduction step, the over
reduction providing the corresponding amine 19, as the
major product, was observed under the other solvent
system, such as methylene chloride, THF or toluene
(Scheme 4).
The mono-phenolic compound 13 was subjected to an
aromatic oxidation with PhI(OAc)2 or PIFA under various
reaction conditions. Among them, it was found that treat-
ment of 13 with PhI(OAc)2 in hexafluoroisopropanol as
the solvent afforded the desired dienone 149 in the best
yield (49%).10 1,4-Reduction of the dienone with copper
hydride11 to the corresponding cyclohexanone 1512 was
achieved, in 65% yield, by using the same reaction condi-
tions as for the synthesis of TAN1251A.7 After protection
of the carbonyl group of 15, the benzyl group of the result-
ing amide was removed with palladium hydroxide under
the hydrogenolysis conditions to give the phenolic com-
pound 17. O-Alkylation of 17 with prenyl bromide in the
presence of sodium hydride in THF gave the prenyl ether
Me
N
N
i
ii
O
18
TAN1251C
O
O
20
Scheme 4 Reagents and conditions: (i) DIBALH, Et2O, –78 °C
(70%); (ii) 1 M HCl aq, acetone, r.t. (70%).
Synlett 2005, No. 2, 328–330 © Thieme Stuttgart · New York

330
H. Mizutani et al.
LETTER
5.01 (2 H, s), 6.19 (1 H, dd, J = 1.8, 10.1 Hz), 6.31 (1 H, dd,
J = 1.8, 10.1 Hz), 6.75 (1 H, dd, J = 3.1, 10.1 Hz), 6.85 (2 H,
d, J = 8.6 Hz), 6.90 (1 H, dd, J = 3.1, 10.1 Hz), 7.06 (2 H, d,
J = 8.6 Hz), 7.31–7.43 (5 H, m). 13C NMR (CDCl3): d =
33.5, 35.9, 44.9, 59.3, 61.6, 63.2, 69.7, 70.4, 114.4, 124.4,
126.7, 127.2, 127.7, 128.3, 129.9, 132.4, 136.9, 149.0,
150.8, 157.0, 169.7, 185.1. IR (KBr): 2970, 1668, 1650,
1510, 1452, 1396, 1310, 1235, 1178, 1095, 1005, 864 cm–1.
HRMS: m/z calcd for C26H26N2O3: 414.1943; found:
414.1940. Anal. Calcd for C26H26N2O3: C, 75.34; H, 6.32; N,
6.76. Found: C, 75.37; H, 6.48; N, 6.71.
Again, deprotection of the ketal group under the acidic
conditions afforded TAN1251C.14 The spectroscopic data
including specific optical rotation {[a]D +23 (c 0.76,
MeOH); lit.1 [a]D +24 (c 0.44, MeOH); lit.4 [a]D +23 (c
0.45, MeOH)} were identical with those reported.
In summary, we disclosed herein the facile synthesis of
TAN1251C and D in optically pure forms starting from
the dimeric tyrosine derivative. This synthesis demon-
strated that an aromatic oxidation with hypervalent re-
agent was applicable to the secondary amines to construct
a problematic carbon-nitrogen bond.
(10) In the aromatic oxidation, PIFA instead of PhI(OAc)2 gave
the dienone 14 in only 15% yield.
(11) (a) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989,
111, 8818. (b) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R.
Tetrahedron Lett. 1998, 39, 4627. (c) Mori, A.; Fujita, A.;
Kajiro, H.; Nishihara, Y.; Hiyama, T. Tetrahedron 1999, 55,
4573.
Acknowledgment
This work was supported in part by grant from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
(12) Spectroscopic data of compound 15: white solid; mp 134–
135 °C; [a]D –52.6 (c 1.23, CHCl3). 1H NMR (CDCl3): d =
1.91 (1 H, dd, J = 4.3, 12.9 Hz), 1.98–2.01 (3 H, m), 2.21 (1
H, dd, J = 2.3, 12.9 Hz), 2.26–2.55 (5 H, m), 2.81 (1 H, dd,
J = 5.4, 14.2 Hz), 2.92 (3 H, s), 3.19 (1 H, d, J = 10.7 Hz),
3.39–3.50 (2 H, m), 3.77 (1 H, br m), 3.99 (1 H, t, J = 6.3
Hz), 5.03 (2 H, s), 6.89 (2 H, d, J = 8.7 Hz), 7.32 (2 H, d,
J = 8.7 Hz), 7.29–7.44 (5H, m). 13C NMR (CDCl3): d = 29.5,
33.1, 35.9, 37.4, 38.3, 39.0, 39.7, 42.0, 59.5, 61.8, 66.0, 69.8,
70.4, 114.4, 127.3, 127.7, 128.3, 129.9, 133.5, 137.0, 156.9,
170.5, 209.5. IR (KBr): 2955, 2868, 1715, 1650, 1510, 1456,
1392, 1310, 1235, 1176, 1024, 826 cm–1. HRMS: m/z calcd
for C26H30N2O3: 418.2256; found: 418.2245. Anal. Calcd for
C26H30N2O3: C, 74.61; H, 7.22; N, 6.69. Found: C, 74.64; H,
7.24; N, 6.64.
(13) Spectroscopic data of TAN1251D: colorless oil; [a]D +24.7
(c 0.20, MeOH). 1H NMR (CDCl3): d = 1.67 (1 H, dd,
J = 5.8, 13.7 Hz), 1.73 (3 H, s), 1.79 (3 H, s), 1.86 (1 H, d,
J = 13.7 Hz), 1.98–2.03 (2 H, m), 2.14 (3 H, s), 2.18–2.27 (2
H, m), 2.33–2.59 (5 H, m), 2.63–2.68 (2 H, m), 2.98–3.05 (2
H, m), 3.18–3.35 (3 H, m), 4.47 (2 H, d, J = 6.6 Hz), 5.46–
5.51 (1 H, m), 6.82 (2 H, d, J = 8.6 Hz), 7.07 (2 H, d, J = 8.6
Hz). 13C NMR (CDCl3): d = 18.2, 25.8, 33.0, 33.2, 37.9,
39.2, 39.5, 41.3, 42.4, 52.2, 61.2, 61.8, 64.7, 65.0, 65.7,
114.6, 119.7, 129.7, 131.8, 138.0, 157.4, 210.8. IR (thin
film): 2925, 2853, 1719, 1611, 1520, 1458, 1377, 1297,
1238, 1010, 772 cm–1. HRMS: m/z calcd for C24H34N2O2:
382.2620; found: 382.2648.
(14) Spectroscopic data of TAN1251C: colorless oil; [a]D +23.0
(c 0.76, MeOH). 1H NMR (CDCl3): d = 1.74 (3 H, s), 1.79 (3
H, s), 1.81–1.84 (1 H, m), 1.88 (1 H, dd, J = 5.1, 13.0 Hz),
1.98 (1 H, ddd, J = 4.6, 10.2, 13.0 Hz), 2.51 (3 H, s), 2.16–
2.64 (7 H, m), 2.79 (1 H, dd, J = 1.3, 11.5 Hz), 3.20 (1 H, dd,
J = 3.0, 11.5 Hz), 3.21 (2 H, s), 3.39–3.44 (1 H, m), 4.48 (2
H, d, J = 6.8 Hz), 5.24 (1 H, s), 5.47–5.52 (1 H, m), 6.83 (2
H, d, J = 8.6 Hz), 7.08 (2 H, d, J = 8.6 Hz). 13C NMR
(CDCl3): d = 18.2, 25.8, 34.6, 37.3, 37.8, 39.5, 40.3, 41.4,
42.9, 52.2, 59.0, 64.7, 71.4, 114.4, 119.9, 127.8, 128.2,
129.8, 131.9, 138.0, 157.1, 211.6. IR (thin film): 3415, 2928,
2865, 1716, 1678, 1642, 1610, 1508, 1445, 1376, 1298,
1234, 1174, 1112, 1057 cm–1. HRMS: m/z calcd for
C24H32N2O2: 380.2464; found: 380.2453.
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Synlett 2005, No. 2, 328–330 © Thieme Stuttgart · New York