Synthesis of (-)-TAN1251A using 4-hydroxy-L-proline as a chiral source

Article abstract of DOI:10.1016/S0040-4020(02)01292-9

A new synthetic route of (-)-TAN1251A possessing an antimuscarinic activity was developed on the basis of alkylation of a trans-4-hydroxy-L-proline derivative and the subsequent construction of an azaspiro ring as key steps.

Full text of DOI:10.1016/S0040-4020(02)01292-9

Tetrahedron 58 (2002) 9871–9877
Synthesis of (2)-TAN1251A using 4-hydroxy-L-proline
as a chiral source
*
Shinji Nagumo, Aoi Matoba, Yusuke Ishii, Syunji Yamaguchi, Noriaki Akutsu,
†
Hideto Nishijima, Atsushi Nishida and Norio Kawahara
*
Hokkaido College of Pharmacy, Katuraoka 7-1, Otaru 047-0264, Japan
Received 19 August 2002; accepted 26 September 2002
Abstract—A new synthetic route of (2)-TAN1251A possessing an antimuscarinic activity was developed on the basis of alkylation of a
trans-4-hydroxy-L-proline derivative and the subsequent construction of an azaspiro ring as key steps. q 2002 Published by Elsevier Science
Ltd.
TAN1251A and B are alkaloids isolated from a culture of
Penicillium thomii RA-89 (Fig. 1).1 These compounds
exhibit cholinergic activity and cause acetylcholine-induced
contraction of the guinea-pig ileum (ED50: 8.0 and 10.0 nM,
respectively). The affinity of TAN1251B to a muscarinic
acetylcholine receptor is stronger than that of atropine.
TAN1251A shows selective inhibition toward the M1
subtype of the muscarinic receptor. Their structural features
are very interesting for organic chemists because the central
tricyclic skeleton that includes a 1-azaspiro[4.5]decane ring
is unique. In 1998, we reported in a preliminary communi-
cation the first total synthesis of (^)-TAN1251A.2,3 After
the publication of our report, a few groups reported total
syntheses of (2)-TAN1251A in which the construction of
an enantiomeric 1-azaspiro[4.5]decane skeleton was
regarded as a key step. Snider et al. constructed the skeleton
by a 1,3-dipolar cycloaddition of nitron in the syntheses of
optically active TAN1251A, B, C and D.4 In Wardrop’s
synthesis of (2)-TAN1251A, a spiro-cyclization of N-meth-
oxy-N-acylnitrenium ion was used for the ring construc-
tion.5 Honda et al. also achieved the formal synthesis of
(2)-TAN1251A based on the construction of the ring
system by spiro-cyclization using aromatic oxidation with a
hypervalent iodine reagent.6 In all of these methods,
tyrosine was used as a chiral source. Another possible
chiral source of an enantiomeric 1-azaspiro[4.5]decane
skeleton is trans-4-hydroxy-L-proline. We report here the
synthesis of (2)-TAN1251A based on the alkylation of
4-hydroxyproline and the subsequent construction of a
spiro-ring system by an intramolecular aldol reaction.
Scheme
1 shows our retrosynthetic analysis of
(2)-TAN1251A. We have already achieved a conversion
of tricyclic amide (^)-20 into racemic TAN1251A.2,3
Wardrop’s group has also applied this synthetic route to
chiral synthesis.5 Consequently, (þ)-20 is our target
molecule and can also be prepared from (þ)-16 according
to our racemic route. Compound (þ)-16 should be
obtainable from 10 via installation of an azide group and
N-alkylation. Excision of the cyclohexanone ring from 10 in
a retrosynthetic sense leads to aldehyde 5, which might be
easily prepared by alkylation of 1 followed by a few steps of
functional group interconversion.
Alkylation of 1 with 4-iodo-1-butene was carried out by
using 2.5 equiv. of LDA to afford 2a (67%) and 2b (15%)
(Scheme 2). The stereochemical finding (2a/2b¼4.5:1)
surprised us because the ratio of the products had been
found to be ca. 2.7:1 in the case of using LDA (1.2 equiv.).7
The selectivity should be important for carrying out a
synthetic study of TAN1251B. However, both of the
products 2a and 2b can be used in the synthetic study of
TAN1251A. Next, DIBAH reduction of 2a was carried out
to give 3a, which was converted into 4a by TPAP oxidation.
Figure 1.
Keywords: (2)-TAN1251A; anti-muscarinic activity; synthesis;
1-azaspiro[4.5]decane; trans-4-hydroxy-L-proline.
*
Corresponding authors. Tel.: þ81-134-62-1842; fax: þ81-134-62-5161;
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.
†
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01292-9

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S. Nagumo et al. / Tetrahedron 58 (2002) 9871–9877
Scheme 1. Retrosynthetic route of (2)-TAN1251A.
Wacker oxidation of 4a afforded ketone 5a in high yield
when sufficient oxygen was continuously supplied to the
reaction mixture by a gas inlet tube. Otherwise, migration of
a double bond occurred to give a mixture of olefinic isomers
6a, and as a result 5a was obtained in 62% yield. Exposure
of 5a to alkaline conditions produced aldol 7a, which was
converted to mesylate 8a. When crude 8a was subjected to
column chromatography with silica gel, elimination
occurred to give enone 9a in 78% yield. Similarly, 2b
was successfully converted into 9b in 45% overall
yield. Catalytic hydrogenation of 9a and 9b was carried
out by using 20% Pd(OH)2–C in benzene to afford ketone
10.
reaction of 12 with DPPA8 afforded azide 13 in 84% yield.
In order to confirm the optical purity, 13 was subjected to
removal of BOC group to give 14, which was converted into
15 by benzoylation. The optical purity of 15 was found to be
.99% ee by HPLC analysis with a chiral column.
Alkylation of 14 with ethyl bromoacetate proceeded
1
smoothly to provide ester (þ)-16 in high yield. Its H and
13C NMR spectroscopic data were identical with those of
racemic 16, which is a synthetic intermediate of racemic
TAN1251A. Furthermore, (þ)-16 was converted into
tricyclic amide (þ)-20 ([a]2D5¼þ18.1 (CHCl3); reported:9
[a]3D0¼þ15.3 (CHCl3)) by the sequence of catalytic
hydrogenation, hydrolysis of the ester group, lactam ring
formation and methylation. Since Wardrop’s group
has already reported the conversion of (þ)-20
into (2)-TAN1251A using our racemic procedure, we
developed a completely original route of (2)-TAN1251A.
Acetalization of 10 with ethyleneglycol provided acetal 11,
which was subjected to desilylation by a conventional
method to give alcohol 12 (Scheme 3). Mitsunobu-type
Scheme 2. (a) LDA (2.5 equiv.), HMPA (10 equiv.), 4-iodo-1-butene, THF, 2788C; (b) DIBAH, toluene, 2308C; (c) TPAP, NMO, CH2Cl2; (d) PdCl2, CuCl2,
O2, H2O, DMF; (e) KOH, EtOH, 08C; (f) MsCl, Et3N, CH2Cl2; (g) silica gel column chromatography; (h) 20% Pd(OH)2–C, H2, benzene.

S. Nagumo et al. / Tetrahedron 58 (2002) 9871–9877
9873
Scheme 3. (a) (CH2OH)2, TsOH, benzene, reflux; (b) TBAF, THF; (c) DPPA, Ph3P, DEAD, THF; (d) TFA; (e) PhCOCl, Et3N, CH2Cl2; (f) BrCH2COOEt,
K2CO3, CH3CN; (g) 5% Pd–C, H2, MeOH; (h) LiOH, H2O; (I) DPPA, Et3N, DMF; (j) CH3l, NaH, THF.
1. Experimental
1.1. General methods
calcd for C29H40NO3Si (Mþ2CH2OH) 478.2775; found
478.2750.
1.1.2. tert-Butyl (2R,4R)-2-(but-3-enyl)-4-tert-butyldi-
phenylsilyloxy-2-hydroxymethyl-1-pyrrolidinecarboxyl-
ate (3b). [a]2D3¼þ13.6 (c¼1.00, CHCl3). 1H NMR (CDCl3)
d: 7.66–7.63 (m, 4H), 7.48–7.26 (m, 6H), 5.70 (ddt,
J¼16.85, 10.26, 6.59 Hz, 1H), 5.29 (d, J¼10.0 Hz, 1H),
4.98–4.83 (m, 2H), 4.20 (m, 1H), 3.97 (d, J¼10.0 Hz, 1H),
3.68 (t, J¼10.0 Hz, 1H), 3.40–3.23 (m, 2H), 2.07–1.66 (m,
6H), 1.43 (s, 9H), 1.17 (s, 9H). The peak at 5.29 ppm was
disappeared by addition of D2O. 13C NMR (CDCl3) d: 155.8
(s), 138.3 (d), 135.7 (d, 4C), 133.2 (s, 2C), 130.0 (d, 2C),
127.8 (d, 4C), 114.4 (t), 80.2 (s), 69.45 (t), 69.35 (d), 67.3
(s), 56.4 (t), 43.5 (t), 32.4 (t), 28.4 (q, 3C), 27.5 (t), 26.8
(q, 3C), 19.0 (s). IR (neat) cm21: 3390, 1736, 1671, 1591.
EI-MS m/z: 509 (Mþ), 478, 422. HR-MS m/z: calcd for
C30H43NO4Si 509.2959; found 509.2937.
The melting points were determined on Yanaco micro
melting point apparatus and were uncorrected. Optical
rotation was measured on JASCO DIP-370. IR spectra were
recorded on JASCO FT/IR-7000 spectrometer. NMR
spectra were recorded on a JEOL JNM-GX270 spectrometer
using tetramethylsilane as an internal standard. Chemical
shifts are given in ppm. The following abbreviations
are used: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼
multiplet, br¼broad. MS spectra were measured on a
Hitachi M-2000 mass spectrometer. Column chroma-
tography was carried out on Merck’s Silica gel 60
(70–230 mesh ASTM).
1.1.1. tert-Butyl (2S,4R)-2-(but-3-enyl)-4-tert-butyldi-
phenylsilyloxy-2-hydroxymethyl-1-pyrrolidinecarboxyl-
ate (3a). To a solution of 2a (2.06 g, 3.83 mmol) in toluene
(10 ml) was added dropwise DIBAH (1 M in toluene,
9.6 ml, 9.6 mmol) at 2788C under an argon atmosphere.
After being stirred for 2 h, the reaction was quenched with a
small amount of H2O and filtered. The filtrate was
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane/AcOEt (4:1) to give 3a (1.67 g, 3.28 mmol, 86%) as
1.1.3. tert-Butyl (2S,4R)-2-(but-3-enyl)-4-tert-butyldi-
phenylsilyloxy-2-formyl-1-pyrrolidinecarboxylate (4a).
To a mixture of 3a (1.40 g, 2.75 mmol), molecular sieves
˚
4 A (3 g) and CH2Cl2 (60 ml) was added N-methylmorpho-
line N-oxide (NMO, 487 mg, 4.13 mmol) and tetrapropyl-
ammonium perruthenate (TPAP, 96.7 mg, 0.28 mmol) at
room temperature. After being stirred for 2 h, the reaction
mixture was diluted with ether and filtered through a florisil.
The filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel eluted with hexane/AcOEt (4:1) to give 4a (1.30 g,
2.56 mmol, 93%) as a colorless oil. [a]2D3¼þ2.1 (c¼1.04,
a colorless oil. [a]D23¼þ15.6 (c¼1.13, CHCl3). H NMR
1
(CDCl3, ratio of conformers: ca. 4:1) d: 7.70–7.60 (m, 4H),
7.48–7.34 (m, 6H), 5.96–5.78 (m, 1H), 5.17 (d, J¼9.0 Hz,
1H), 5.06 (dd, J¼17.3, 1.4 Hz, 1H), 4.95 (d, J¼10.3 Hz,
1H), 4.40–4.30 and 4.30–4.20 (2m, 1H), 3.62–3.40 (m,
2H), 3.35 (d, J¼4.4 Hz, 2H), 2.35–1.90 (m, 6H), 1.30 (s,
9H), 1.07 (s, 9H). The peak at 5.17 ppm was disappeared
by addition of D2O. 13C NMR (CDCl3) d: 155.8 (s), 138.5
(d), 135.7 (d, 4C), 133.6 (s, 2C), 129.8 (d, 2C), 127.7
(d, 4C), 114.4 (t), 80.2 (s), 69.7 (d), 68.7 (t), 67.6 (s),
56.7 (t), 41.9 (t), 31.7 (t), 29.1 (t), 28.4 (q, 3C), 26.9 (q,
3C), 19.0 (s). IR (neat) cm21: 3396, 1671, 1660, 1591.
EI-MS m/z: 478 (Mþ2CH2OH), 422, 378. HR-MS m/z:
1
CHCl3). H NMR (CDCl3, ratio of conformers: ca. 2:1) d:
9.42 and 9.26 (2s, 1H), 7.68–7.59 (m, 4H), 7.49–7.34 (m,
6H), 5.94–5.77 (m, 1H), 5.14–4.93 (m, 2H), 4.41–4.29 (m,
1H), 3.76 and 3.54 (2ddd, J¼11.5, 6.4, 2.0 Hz, 1H), 3.46–
3.36 and 3.34–3.22 (2m, 1H), 2.40–1.85 (m, 6H), 1.41 and
1.40 (2s, 9H), 1.07 and 1.06 (2s, 9H). 13C NMR (CDCl3,
ratio of conformers: ca. 2:1) d: 199.8 and 198.8 (2d), 153.9
and 153.1 (2s), 138.1 and 137.9 (2d), 135.6 (d, 4C), 133.2
and 133.1 (2s), 130.0 (d, 2C), 128.1 (d, 4C), 114.6 (t), 81.2

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S. Nagumo et al. / Tetrahedron 58 (2002) 9871–9877
and 80.2 (2s), 70.4 and 69.4 (2d), 70.3 (d), 55.6 (t), 41.4 and
40.3 (2t), 32.2 and 31.6 (2t), 28.5 (t), 28.3 and 28.2 (2q, 3C),
26.8 (q, 3C), 19.0 (s). IR (neat) cm21: 1742, 1696. EI-MS
m/z: 507 (Mþ), 480, 424. HR-MS m/z: calcd for
C30H41NO4Si 507.2803; found 507.2823.
d: 208.4 and 207.5 (2s), 202.1 (d), 154.8 and 153.8 (2s),
135.9 (d, 4C), 133.23 and 133.17 (s, 2C), 130.3 (d, 2C),
128.2 (d, 4C), 81.7 and 80.8 (2s), 70.8 and 70.0 (2d), 70.8
(d), 56.7 and 56.4 (2t), 44.7 and 44.2 (2t), 38.9 and 38.2 (2t),
30.1 and 29.8 (2q), 28.5 (2q, 3C), 27.6 and 27.4 (2t), 27.1 (q,
3C), 19.2 (s). IR (neat) cm21: 1720, 1700, 1675. EI-MS m/z:
523 (Mþ), 494, 438, 410. HR-MS m/z: calcd for
C30H41NO5Si 523.2751; found 523.2734.
1.1.4. tert-Butyl (2R,4R)-2-(but-3-enyl)-4-tert-butyldi-
phenylsilyloxy-2-formyl-1-pyrrolidinecarboxylate (4b).
1
[a]2D3¼þ2.1 (c¼1.26, CHCl3). H NMR (CDCl3, ratio of
conformers: ca. 2:1) d: 9.85 and 9.81 (2s, 1H), 7.68–7.58
(m, 4H), 7.52–7.38 (m, 6H), 5.82–5.65 (m, 1H), 5.02–4.85
(m, 2H), 4.26 (br s, 1H), 3.78 and 3.56 (2d, J¼11.7 Hz, 1H),
3.31 and 3.19 (2dd, J¼11.7, 3.7 Hz, 1H), 2.33–1.69 (m,
6H), 1.47 and 1.46 (2s, 9H), 1.04 (s, 9H). 13C NMR (CDCl3,
ratio of conformers: ca. 2:1) d: 203.2 and 202.8 (2d), 154.3
and 153.6 (2s), 137.9 and 137.5 (2d), 135.6 (d, 4C), 133.03
and 132.98 (2s, 2C), 130.0 (d, 2C), 127.8 (d, 4C), 114.9 and
114.6 (2t), 81.0 and 80.2 (2s), 71.1 and 70.8 (2s), 70.4 and
69.8 (2d), 56.6 (t), 44.3 and 43.2 (2t), 31.7 and 30.8 (2t),
28.3 (q, 3C), 27.8 and 27.4 (t), 26.8 (q, 3C), 18.9 (s).
IR (neat) cm21: 1734, 1694, 1642. EI-MS m/z: 478
(Mþ2CHO), 433, 422, 394, 378. HR-MS m/z: calcd for
C29H40NO3Si (Mþ2CHO) 478.2775; found 478.2765.
1.1.7. tert-Butyl (3S,5R)-3-tert-butyldiphenylsilyloxy-6-
hydroxy-8-oxo-1-azaspiro[4.5]decane-1-carboxylate
(7a). To a solution of 5a (1.00 g, 1.90 mmol) in EtOH
(90 ml) was added KOH (64 mg, 0.96 mmol) at 08C. After
being stirred for 1.5 h, the reaction mixture was quenched
with saturated aqueous NH4Cl. After removal of EtOH by
evaporation, the mixture was extracted with ether. The
extract was washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane/AcOEt (4:1) to give 7a (798 mg, 1.52 mmol, 80%)
as white crystals. Mp 131–1328C (AcOEt/hexane). [a]2D0¼
213.6 (c¼1.02, CHCl3). Since 7a is a mixture of two
1
epimers at C6 position including two conformers, its H
1
and 13C NMR spectroscopic data are complex. H NMR
1.1.5. tert-Butyl (2S,4R)-4-tert-butyldiphenylsilyloxy-2-
formyl-2-(3-oxobutyl)-1-pyrrolidinecarboxylate (5a). A
mixture of CuCl (203 mg, 2.05 mmol), PdCl2 (100 mg,
0.56 mmol), H2O (0.5 ml) and DMF (7 ml) was stirred for
1 h at room temperature under an oxygen atmosphere. To
the mixture was added dropwise a solution of 4a (1.00 g,
1.97 mmol) in DMF (6 ml) with continuous introduction of
an oxygen by a gas inlet tube. After being further stirred for
5 h, the reaction mixture was quenched with saturated
aqueous NaHCO3 and saturated aqueous NH4Cl and
extracted with ether and hexane (1:1). The extract was
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on
silica gel eluted with hexane/AcOEt (17:3) to give 5a
(952 mg, 1.82 mmol, 92%) as a colorless oil. [a]2D5¼25.9
(c¼1.20, CHCl3). 1H NMR (CDCl3, ratio of conformers: ca.
3:2) d: 9.28 and 9.22 (2s, 1H), 7.70–7.60 (m, 4H), 7.52–
7.38 (m, 6H), 4.46–4.36 (m, 1H), 3.74 and 3.57 (2dd,
J¼11.7, 6.1 Hz, 1H), 3.45 and 3.36 (2dd, J¼11.7, 3.7 Hz,
1H), 2.88–2.26 (m, 4H), 2.16 and 2.14 (2s, 3H), 2.06–1.73
(m, 2H), 1.42 and 1.41 (2s, 9H), 1.08 and 1.07 (2s, 9H). 13C
NMR (CDCl3, ratio of conformers: ca. 3:2) d: 207.7 and
207.2 (2s), 198.3 and 197.9 (2d), 154.1 and 153.0 (2s), 135.5
(d, 4C), 133.0 and 132.7 (2s, 2C), 130.0 (d, 2C), 127.8 (d,
4C), 81.5 and 80.4 (2s), 70.8 and 69.6 (2d), 70.2 and 69.9
(2s), 55.9 and 55.8 (2t), 41.3 and 41.1 (2t), 38.9 and 38.7
(2t), 29.8 (q), 28.1 (q, 3C), 26.9 (t), 26.7 (q, 3C), 18.9 (s). IR
(neat) cm21: 1735, 1715, 1696. EI-MS m/z: 524 (Mþþ1),
494, 468, 424. HR-MS m/z: calcd for C30H42NO5Si (Mþþ1)
524.2829; found 524.2805.
(CDCl3) d: 7.68–7.59 (m, 4H), 7.49–7.35 (m, 6H), 4.86 (br
s, 1H), 4.44–4.35 (m, 1H), 3.75–3.27 (m, 2H), 2.80–1.92
(m, 9H), 1.44 (s, 9H), 1.09 (s, 9H). 13C NMR (CDCl3) d:
207.9 (s), 153.6 (s), 135.6 (d, 4C), 133.4 (s, 2C), 129.9
(d, 2C), 127.8 (d, 4C), 79.8 (s), 69.7 (d), 67.6 (d), 67.1 (s),
57.2 (t), 47.0 (t), 38.5 (t), 36.4 (t), 28.5 (q, 3C), 28.0 (t),
26.9 (q, 3C), 19.0 (s). IR (CHCl3) cm21: 3425, 1710. EI-MS
m/z: 523 (Mþ), 437, 410. HR-MS m/z: calcd for
C30H41NO5Si 523.2752; found 523.2764. Anal. Calcd for
C30H41NO5Si C 68.81, H 7.89, N 2.68. Found: C 69.10, H
8.09, N 2.56.
1.1.8. tert-Butyl (3R,5R)-3-tert-butyldiphenylsilyloxy-6-
hydroxy-8-oxo-1-azaspiro[4.5]decane-1-carboxylate
(7b). Mp 125–1268C (AcOEt/hexane). [a]2D0¼þ11.6
(c¼1.02, CHCl3). Since 7b is a mixture of two epimers at
C6 position including two conformers, its 1H and 13C NMR
spectroscopic data are complex. 1H NMR (CDCl3) d: 7.72–
7.60 (m, 4H), 7.52–7.37 (m, 6H), 4.92 and 4.60 (2br s, 1H),
4.33–4.25 and 4.17–4.02 (2m, 1H), 3.76–3.33 (m, 3H),
2.86–1.76 (m, 8H), 1.44 (s, 9H), 1.07 (s, 9H). 13C NMR
(CDCl3) d: 207.6 (s), 153.3 (s), 135.6 (d, 4C), 132.6 (s, 2C),
130.2 (d, 2C), 127.9 (d, 4C), 80.0 (s), 69.5 (d), 68.5 (d), 67.2
(d), 55.8 (t), 48.0 (t), 38.11 (t), 38.06 (t), 29.7 (t), 28.4 (q,
3C), 26.7 (q, 3C), 18.9 (s). IR (CHCl3) cm21: 3430, 1720,
1694. EI-MS m/z: 523 (Mþ), 450, 440, 422. HR-MS m/z:
calcd for C30H41NO5Si 523.2752; found 523.2780. Anal.
Calcd for C30H41NO5Si: C 68.81, H 7.89, N 2.68. Found: C
68.93, H 8.06, N 2.60.
1.1.9. tert-Butyl (3S,5R)-3-tert-butyldiphenylsilyloxy-8-
oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylate (9a). To a
solution of 7a (770 mg, 1.47 mmol) in CH2Cl2 (3 ml) was
successively added methanesulfonyl chloride (0.15 ml,
1.8 mmol) and Et3N (0.3 ml, 2.25 mmol) at 08C under an
argon atmosphere. After being stirred for 15 min at room
temperature, the reaction mixture was quenched with
saturated aqueous NaHCO3 and extracted with ether. The
extract was washed with brine, dried over MgSO4 and
1.1.6. tert-Butyl (2R,4R)-4-tert-butyldiphenylsilyloxy-2-
formyl-2-(3-oxobutyl)-1-pyrrolidinecarboxylate
(5b).
1
[a]2D2¼þ11.5 (c¼1.02, CHCl3). H NMR (CDCl3, ratio of
conformers: ca. 1:1) d: 9.77 and 9.75 (2s, 1H), 7.65–7.56
(m, 4H), 7.48–7.34 (m, 6H), 4.32–4.20 (m, 1H), 3.77 and
3.56 (2d, J¼11.7 Hz, 1H), 3.30 and 3.20 (2dd, J¼11.7,
3.9 Hz, 1H), 2.55–1.76 (m, 6H), 2.09 (s, 3H), 1.48 (s, 9H),
1.04 (s, 9H). 13C NMR (CDCl3, ratio of conformers: ca. 1:1)

S. Nagumo et al. / Tetrahedron 58 (2002) 9871–9877
9875
concentrated under reduced pressure to give crude
mesylate 8a. The crude was purified by column
chromatography on silica gel eluted with hexane/AcOEt
(17:3) to give enone 9a (578 mg, 1.14 mmol, 78%) as white
crystals.
1.1.12. (3R)-Dispiro[1-tert-butoxycarbonyl-3-tert-butyl-
diphenylsilyloxypyrrolidine-5,10-cyclohexane-40,200-1,3-
dioxolane] (11). A mixture of 10 (6.75 g, 13.3 mmol),
ethylene glycol (1.5 ml, 26.6 mmol), TsOH·H2O (230 mg,
1.33 mmol) and benzene (25 ml) was refluxed for 3 h fixed
with Dean-stark apparatus. After being cooled to room
temperature, the reaction mixture was quenched with
saturated aqueous NaHCO3 and extracted with ether. The
extract was washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane/AcOEt (17:3) to give 11 (6.39 g, 11.6 mmol, 87%)
as white crystals. Mp 92–938C (AcOEt/hexane). [a]2D0¼
23.7 (c¼1.02, CHCl3). 1H NMR (CDCl3) d: 7.66–7.61 (m,
4H), 7.44–7.32 (m, 6H), 4.21 (quintet, J¼4.9 Hz, 1H), 3.92
(s, 4H), 3.59–3.30 (m, 2H), 3.00–2.52 (m, 2H), 2.08 (dd,
J¼13.2, 4.6 Hz, 1H), 1.89–1.47 (m, 7H), 1.46 (s, 9H), 1.04
(s, 9H). 13C NMR (CDCl3, ratio of conformers: ca. 1:1) d:
154.3 and 153.1 (2s), 135.7 (d, 4C), 133.7 (s, 2C), 129.8 (d,
2C), 127.7 (d, 4C), 108.0 (s), 79.6 and 78.7 (2s), 69.9 and
69.2 (2d), 64.3 (t, 2C), 64.1 (t), 62.9 and 62.7 (2s), 55.6 (t),
44.5 and 43.7 (2t), 32.7 (t), 31.8 (t), 31.5 and 30.6 (2t), 28.6
(q, 3C), 26.8 (q, 3C), 19.0 (s). IR (neat) cm21: 1688. EI-MS
m/z: 551 (Mþ), 438. HR-MS m/z: calcd for C32H45NO5Si
551.3065; found 551.3054. Anal. Calcd for C32H45NO5Si: C
69.67, H 8.22, N 2.54. Found: C 69.78, H 8.40, N 2.63.
Mp 146–1478C (AcOEt/hexane). [a]2D3¼25.0 (c¼1.00,
1
CHCl3). H NMR (CDCl3, ratio of conformers: ca. 3:2) d:
7.68–7.58 (m, 4H), 7.50–7.35 (m, 6H), 6.74 and 6.62 (2d,
J¼10.1 Hz, 1H), 5.89 and 5.82 (2d, J¼10.1 Hz, 1H), 4.45–
4.34 (br s, 1H), 3.70–3.30 (m, 2H), 3.02–2.14, 1.83–1.66
(m, 6H), 1.44 and 1.42 (2s, 9H), 1.07 (s, 9H). 13C NMR
(CDCl3, ratio of conformers: ca. 3:2) d: 198.5 and
198.3 (2s), 157.2 and 157.0 (2d), 153.4 (s), 135.6 (d, 4C),
133.2 and 132.9 (2s, 2C), 130.0 and 129.9 (2d, 2C), 127.9
(d, 4C), 126.9 and 126.5 (2d), 80.7 and 80.0 (2s), 70.9
and 70.1 (2d), 62.2 and 62.1 (2s), 56.2 (t), 42.8 and 42.1 (t),
35.5 and 35.2 (t), 31.5 and 30.3 (t), 28.4 (q, 3C), 26.8
(q, 3C), 18.9 (s). IR (CHCl3) cm21: 1670. EI-MS m/z:
506 (Mþþ1), 450. HR-MS m/z: calcd for C30H40NO4Si
(Mþþ1) 506.2724; found 506.2752. Anal. Calcd for
C30H39NO4Si: C 71.26, H 7.77, N 2.77. Found: C 71.73,
H 7.96, N 2.72.
1.1.10. tert-Butyl (3R,5R)-3-tert-butyldiphenylsilyloxy-8-
oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylate (9b). Mp
146–1478C (AcOEt/hexane). [a]2D1¼225.0 (c¼1.00,
1
CHCl3). H NMR (CDCl3, ratio of conformers: ca. 1:1) d:
1.1.13. (3R)-Dispiro[1-tert-butoxycarbonyl-3-hydroxy-
pyrrolidine-5,10-cyclohexane-40,200-1,3-dioxolane] (12).
To a solution of 11 (8.52 g, 15.4 mmol) in THF was
added a 1 M solution of TBAF (42 ml, 42.0 mmol) at 08C
under an argon atmosphere. The solution was further stirred
for 5 h, then quenched with saturated aqueous NH4Cl and
extracted with ether. The extract was washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on
silica gel eluted with hexane/AcOEt (1:2) to give 12 (4.80 g,
15.3 mmol, 99%) as white crystals. Mp 215–2168C
7.68–7.54, 7.51–7.32 (m, 10H), 7.15 and 7.02 (2d,
J¼10.3 Hz, 1H), 5.92 and 5.85 (2d, J¼10.3 Hz, 1H), 4.31
(quintet, J¼4.9 Hz, 1H), 3.67–3.30 (m, 2H), 3.04–2.88 and
2.81–2.64 (m, 1H), 2.52–2.02 (m, 4H), 1.72–1.55 (m, 1H),
1.45 and 1.41 (2s, 9H), 1.06 (s, 9H). 13C NMR (CDCl3, ratio
of conformers: ca. 1:1) d: 198.5 (s), 158.9 (d), 154.0 (s),
136.1 (d, 4C), 133.7 (s, 2C), 130.4 (d, 2C), 128.3 (d, 4C),
126.9 and 126.4 (2d), 81.1 and 80.4 (2s), 70.5 and 69.8 (2d),
62.1 and 61.9 (2s), 55.5 and 55.2 (2t), 46.4 and 46.1 (2t),
36.0 and 35.7 (2t), 34.3 and 33.2 (2t), 28.8 (q, 3C), 27.2 (q,
3C), 19.4 (s). IR (CHCl3) cm21: 1686. EI-MS m/z: 505
(Mþ), 392. HR-MS m/z: calcd for C30H39NO4Si 505.2646;
found 505.2673.
(AcOEt/hexane). [a]D25¼212.7 (c¼1.03, CHCl3). H NMR
1
(CDCl3) d: 4.38–4.29 (m, 1H), 3.93 (s, 4H), 3.63 (dd,
J¼12.0, 4.6 Hz, 1H), 3.47 (br d, J¼12.0, 1H), 3.00–2.55
(m, 2H), 2.30–1.90 (m, 3H), 1.70–1.22 (m, 6H), 1.48 (s,
9H). 13C NMR (CDCl3, ratio of conformers ca. 1:1) d: 154.4
(s), 107.9 (s), 79.9 and 79.6 (2s), 68.2 and 67.9 (2d), 64.3 (t),
62.9 (s), 55.6 (t), 44.4 (t), 43.9 (t), 32.7 (t), 32.6 (t), 32.2 (t),
31.2 (t), 28.8 (q, 3C). IR (CHCl3) cm21: 3414, 1676. EI-MS
m/z: 313 (Mþ), 158. HR-MS m/z: calcd for C16H27NO5
313.1888; found 313.1913. Anal. Calcd for C16H27NO5: C
61.32, H 8.68, N 4.47. Found: C 61.40, H 8.90, N 4.51.
1.1.11. tert-Butyl (3R)-3-tert-butyldiphenylsilyloxy-8-
oxo-1-azaspiro[4.5]decane-1-carboxylate (10). A mixture
of 9a (100 mg, 0.198 mmol), 20% Pd(OH)2–C (5 mg) and
benzene (25 ml) was stirred under H2 atmosphere for 5 h.
The reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
hexane/AcOEt (17:3) to give 10 (99.3 mg, 0.196 mmol,
99%) as white crystals. Mp 72–738C (hexane). [a]2D0¼25.8
(c¼1.00, CHCl3). 1H NMR (CDCl3, ratio of conformers: ca.
1:1) d: 7.68–7.60 (m, 4H), 7.50–7.34 (m, 6H), 4.33–4.28
(m, 1H), 3.69–3.30 (m, 2H), 3.10–2.60 (m, 2H), 2.50–1.90
(m, 8H), 1.44 (s, 9H), 1.07 (s, 9H). 13C NMR (CDCl3) d:
210.5 (s), 153.3 (s), 135.7 (d, 4C), 133.4 (s, 2C), 129.9 (d,
2C), 127.8 (d, 4C), 79.1 (s), 69.8 and 69.2 (2d), 62.1 and
61.8 (2s), 55.8 (t), 44.6 and 44.3 (2t), 38.6 (t, 2C), 33.3 (t),
1.1.14. (3S)-Dispiro[3-azido-1-tert-butoxycarbonylpyr-
rolidine-5,10-cyclohexane-40,200-1,3-dioxolane] (13). To a
solution of 12 (1.96 g, 6.25 mmol) in THF (60 ml)
were successively added triphenylphosphine (3.36 g,
12.3 mmol), diethyl azodicarboxylate (2.1 ml, 12.3 mmol)
and diphenylphosphoryl azide (2.79 ml, 12.3 mmol). The
reaction mixture was stirred at room temperature for 15 min,
and then concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel eluted
with hexane/AcOEt (9:1) to give 13 (1.77 g, 5.23 mmol,
84%) as white crystals. Mp 106–1078C (hexane). [a]2D0¼
31.9 (t), 28.5 (q, 3C), 26.8 (q, 3C), 19.0 (s). IR (neat) cm21
:
1717, 1694. EI-MS m/z: 508 (Mþþ1), 452, 408. HR-MS
m/z: calcd for C30H42NO4Si (Mþþ1) 508.2881; found
508.2883. Anal. Calcd for C30H41NO4Si: C 70.98, H 8.14, N
2.76. Found: C 71.28, H 8.32, N 2.73.
1
þ8.9 (c¼0.99, CHCl3). H NMR (CDCl3) d: 4.40 (quintet,
J¼5.4 Hz, 1H), 3.93 (s, 4H), 3.76–3.60 (m, 1H), 3.60–3.35

9876
S. Nagumo et al. / Tetrahedron 58 (2002) 9871–9877
(m, 1H), 3.00–2.60 (m, 2H), 2.20 (dd, J¼13.0, 6.35 Hz,
1H), 2.15–2.00 (br s, 1H), 1.86–1.20 (m, 6H), 1.48 (s, 9H).
13C NMR (CDCl3, ratio of conformers ca. 1:1) d: 154.0 (s),
107.7 (s), 80.1 and 79.4 (2s), 64.3 (t, 2C), 62.7 (s), 57.3 and
57.1 (2d), 52.2 (t), 41.4 and 40.5 (2t), 32.7 (t, 2C), 32.6 and
A mixture of 16 (392 mg, 1.21 mmol), 5% Pd–C (trace
amount) and MeOH (4 ml) was stirred under H2 atmosphere
for 3.5 h. The reaction mixture was filtered, and the filtrate
was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with
chloroform/methanol (9:1), which was saturated by ammo-
nia, to give 17 (327 mg, 1.10 mmol, 91%) as a colorless oil.
[a]2D4¼25.8 (c¼1.02, CHCl3). 1H NMR (CDCl3) d: 4.16 (q,
J¼7.2 Hz, 2H), 3.93 (s, 4H), 3.59–3.48 (m, 1H), 3.41 (d,
J¼16.6 Hz, 1H), 3.22 (d, J¼16.6 Hz, 1H), 3.07 (dd, J¼9.3,
6.8 Hz, 1H), 2.79 (dd, J¼9.3, 4.4 Hz, 1H), 2.26 (dd, J¼12.9,
8.1 Hz, 1H), 1.80–1.36 (m, 11H), 1.27 (t, J¼7.2 Hz, 3H).
13C NMR (CDCl3) d: 172.0 (s), 108.3 (s), 64.3 (t), 64.1 (t),
62.8 (s), 60.7 (t), 60.5 (t), 49.5 (t), 48.9 (d), 44.4 (t), 32.6 (t),
32.4 (t), 31.8 (t), 28.7 (t), 14.2 (q). IR (neat) cm21: 3366,
1748. EI-MS m/z: 298 (Mþ), 269. HR-MS m/z: calcd for
C15H26N2O4 298.1891; found 298.1890.
32.4 (2t), 31.4 and 30.9 (2t), 28.5 (q, 3C). IR (CHCl3) cm21
:
2108, 1763, 1692. EI-MS m/z: 338 (Mþ), 239, 101. HR-MS
m/z: calcd for C16H26N4O4 338.1952; found 338.1932.
Anal. Calcd for C16H26N4O4: C 56.79, H 7.74, N 16.56.
Found: C 56.99, H 7.86, N 16.39.
1.1.15. (3S)-Dispiro[3-azido-1-benzoylpyrrolidine-5,10-
cyclohexane-40,200-1,3-dioxolane] (15). A solution of 13
(144 mg, 0.426 mmol) in trifluoroacetic acid (0.5 ml) was
stirred at 2108C for 10 min, and then concentrated under
reduced pressure to give crude amine 14. To a solution of
the crude 14 in CH2Cl2 (2 ml) were successively added
triethylamine (0.2 ml, 1.43 mmol) and benzoyl chloride
(0.06 ml, 0.353 mmol). The mixture was stirred for 1 h at
room temperature, then quenched with saturated aqueous
NH4Cl and extracted with ether. The extract was washed
with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel eluted with hexane/AcOEt
(1:1) to give 15 (101 mg, 0.295 mmol, 69%) as a colorless
oil. [a]2D0¼þ8.1 (c¼1.09, CHCl3). 1H NMR (CDCl3, ratio of
conformers: ca. 2:1) d: 7.38 (s, 5H), 4.20–3.90 (m, 5H),
3.69 and 3.62 (2dd, J¼11.5, 6.0 Hz, 1H), 3.49 and 3.42
(2dd, J¼11.0, 5.3 Hz, 1H), 3.38–3.14 (m, 2H), 2.70–1.97
(m, 2H), 1.90–1.56 (m, 5H), 1.49–1.37 (m, 1H). 13C NMR
(CDCl3, ratio of conformers: ca. 2:1) d: 169.5 (s), 138.6 (s),
129.8 and 129.4 (2d), 128.6 and 128.4 (2d, 2C), 126.3 and
126.2 (2d, 2C), 107.6 (s), 65.2 (s), 64.4 (t, 2C), 57.8 (d), 55.5
and 55.3 (2t), 40.7 (t), 32.6 (t), 32.5 (t), 30.8 (t), 30.5 (t). IR
(neat) cm21: 2108, 1717. EI-MS m/z: 342 (Mþ), 105. HR-
MS m/z: calcd for C18H22N4O3 342.1691; found 342.1662.
1.1.18. (3S)-Dispiro[1,4-diazabicyclo[3.2.1]octan-3-one-
7,10-cyclohexane-40,200-1,3-dioxolane] (19). To a solution
of 17 (951 mg, 3.19 mmol) in H2O (13 ml) was added
lithium hydroxide (84.3 mg, 3.5 mmol). The reaction
mixture was stirred at room temperature for 2 h, and then
concentrated under reduced pressure to give crude amino
acid 18. To a solution of the crude 18 in DMF (40 ml) was
added triethylamine (1.4 ml, 9.96 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 2.5 h, and then concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel eluted with chloroform/metha-
nol (30:1), which was saturated by ammonia, to give 19
(460 mg, 1.83 mmol, 57%) as white crystals. Mp 230–
2318C (AcOEt/hexane). [a]2D5¼þ17.9 (c¼1.00, CHCl3). 1H
NMR (CDCl3) d: 6.44 (br, 1H), 3.95 (s, 4H), 3.85–3.78 (m,
1H), 3.62 (d, J¼18.6 Hz, 1H), 3.53 (d, J¼18.6 Hz, 1H), 3.18
(dd, J¼12.2, 2.7 Hz, 1H), 3.06 (d, J¼12.2 Hz, 1H), 2.01–
1.50 (m, 10H). 13C NMR (CDCl3) d: 170.5 (s), 107.9 (s),
64.31 (t), 64.28 (t), 64.2 (s), 56.2 (t), 55.0 (t), 53.3 (d), 47.8
1.1.16. (3S)-Dispiro[3-azide-1-ethoxycarbonylmethyl-
pyrrolidine-5,10-cyclohexane-40,200-1,3-dioxolane] (16).
Crude amine 14 was prepared from 13 (1.62 g, 4.79
mmol) according to the procedure previously described.
To a solution of 14 in acetonitrile (25 ml) were successively
added potassium carbonate (1.98 g, 14.3 mmol) and ethyl
bromoacetate (0.79 ml, 7.1 mmol). The reaction mixture
was stirred at room temperature for 18 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 purified by column
chromatography on silica gel eluted with hexane/AcOEt
(1:4) to give 16 (1.40 g, 4.32 mmol, 90%) as a colorless oil.
(t), 36.5 (t), 32.8 (t), 32.6 (t), 31.9 (t). IR (CHCl3) cm21
:
1688. EI-MS m/z: 252 (Mþ), 168. HR-MS m/z: calcd for
C13H20N2O3 252.1473; found 252.1481. Anal. Calcd for
C13H20N2O3: C 61.88, H 7.99, N 11.10. Found: C 61.99, H
8.12, N 11.02.
1.1.19. (3S)-Dispiro[1,3-dioxolane-2,10-cyclohexane-
40,700-4-methyl-1,4-diazabicyclo[3.2.1]octan-3-one] (20).
To
a
solution of 55% sodium hydride (12 mg,
0.275 mmol) in THF (1 ml) were successively added a
solution of 19 (59.8 mg, 0.237 mmol) in THF (1 ml) and
iodomethane (0.04 ml, 0.65 mmol) at 08C. The reaction
mixture was further stirred at room temperature for 1 h, then
quenched with saturated aqueous NH4Cl and extracted with
CHCl3. The extract was washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel eluted with chloroform/methanol (30:1), which was
saturated by ammonia, to give 20 (42.1 mg, 0.158 mmol,
67%) as a colorless oil. [a]2D5¼þ18.1 (c¼1.05, CHCl3). 1H
NMR (CDCl3) d: 3.94 (s, 4H), 3.63–3.59 (m, 1H), 3.59 (d,
J¼18.6 Hz, 1H), 3.48 (d, J¼18.6 Hz, 1H), 3.24 (dd, J¼12.2,
2.4 Hz, 1H), 3.05 (d, J¼12.2 Hz, 1H), 2.90 (s, 3H), 1.94–
1.48 (m, 10H). 13C NMR (CDCl3) d: 168.2 (s), 107.9 (s),
1
[a]2D2¼þ22.3 (c¼1.01, CHCl3). H NMR (CDCl3) d: 4.17
(q, J¼7.2 Hz, 2H), 4.10–3.99 (m, 1H), 3.94 (s, 4H), 3.35 (s,
2H), 3.34 (dd, J¼10.0, 6.8 Hz, 1H), 2.97 (dd, J¼10.0,
4.4 Hz, 1H), 2.18 (dd, J¼13.5, 8.4 Hz, 1H), 1.92 (dd,
J¼13.5, 4.1 Hz, 1H), 1.84–1.36 (m, 8H), 1.28 (t, J¼7.2 Hz,
3H). 13C NMR (CDCl3) d: 171.4 (s), 108.0 (s), 64.3 (t), 64.1
(t), 62.5 (s), 60.4 (t), 57.9 (d), 56.6 (t), 49.1 (t), 40.3 (t), 32.5
(t, 2C), 30.1 (t), 29.5 (t), 14.1 (q). IR (neat) cm21: 2108,
1748. EI-MS m/z: 325 (Mþþ1), 297. HR-MS m/z: calcd for
C15H25N4O4 (Mþþ1) 325.1874; found 325.1861.
1.1.17. (3S)-Dispiro[3-amino-1-ethoxycarbonylmethyl-
pyrrolidine-5,10-cyclohexane-40,200-1,3-dioxolane] (17).

S. Nagumo et al. / Tetrahedron 58 (2002) 9871–9877
9877
2. Nagumo, S.; Nishida, A.; Yamazaki, C.; Murashige, K.;
Kawahara, N. Tetrahedron Lett. 1998, 39, 4493.
3. For full report, see: Nagumo, S.; Nishida, A.; Yamazaki, C.;
Matoba, A.; Murashige, K.; Kawahara, N. Tetrahedron 2002,
58, 4917.
64.28 (t), 64.24 (t), 64.1 (s), 60.0 (d), 56.3 (t), 55.1 (t), 45.1
(t), 36.4 (t), 33.3 (q), 32.7 (t), 32.5 (t), 31.9 (t). IR (neat)
cm21: 1647. EI-MS m/z: 266 (Mþ), 237, 113. HR-MS m/z:
calcd for C14H22N2O3 266.1629; found 266.1654.
4. Snider, B. B.; Lin, H. Org. Lett. 2000, 2, 643.
5. Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053.
6. Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Tetrahedron
Lett. 2002, 43, 2411.
Acknowledgements
We thank the staff of Discovery Research Laboratories,
Takeda Chemical Industries Ltd for providing us with a
sample of TAN1251A.
7. Nagumo, S.; Mizukami, M.; Akutsu, N.; Nishida, A.;
Kawahara, N. Tetrahedron Lett. 1999, 40, 3209.
8. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 1977.
References
9. See supporting information in Ref. 5.
1. Shirafuji, H.; Tubotani, S.; Ishimaru, T.; Harada, S. PCT Int.
Appl. WO 9,113,887, 1991; Chem. Abstr. 1992, 116, 39780t.