A total synthesis of (17S)-hexahydro-TMC-69

Article abstract of DOI:10.3987/COM-06-10962

The cdc25A protein phosphatase inhibitor (7R,8R, 10R, 17S)-hexahydro-TMC-69 (1a) has been synthesized in a stereoselective manner, starting from an enantiomerically pure pyranone (3) using Knoevenagel condensation as a key step.

Full text of DOI:10.3987/COM-06-10962

HETEROCYCLES, Vol. 71, No. 3, 2007
597
HETEROCYCLES, Vol. 71, No. 3, 2007, pp. 597 - 607. © The Japan Institute of Heterocyclic Chemistry
Received, 4th December, 2006, Accepted, 29th January, 2007, Published online, 30th January, 2007. COM-06-10962
A TOTAL SYNTHESIS OF (17S)-HEXAHYDRO-TMC-69
Kazutoshi Sugawara,* Yasuhiro Imanishi, and Tomiki Hashiyama
Medicinal Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd. 2-2-50,
Kawagishi, Toda-shi, Saitama 335-8505, Japan E-mail: k-suga@tanabe.co.jp
Abstract
–
The cdc25A protein phosphatase inhibitor (7R,8R,10R,
17S)-hexahydro-TMC-69 (1a) has been synthesized in a stereoselective manner,
starting from an enantiomerically pure pyranone (3) using Knoevenagel
condensation as a key step.
INTRODUCTION
The TMC-69(6H) (hexahydro-TMC-69) (1) is a stabilized saturated analogue of novel antitumor natural
antibiotic TMC-69 (2), which was isolated from a fermentation broth of Chrysosporium sp. TC1068 as a
labile amorphous by Kohno and co-workers.1a,1b The semi-synthetic compound showed cytotoxic activities
in vitro against various tumor cell lines (cf. HCT-116, IC50 = 0.70 µM). It has also been found that 1 has a
potent inhibitory activity against protein phosphatase cdc25A (IC50 = 3.1 µM),2 a novel class of a dual
specificity phosphatase. Recently, phosphatase inhibitors have received considerable attention due to the
crucial role they play in human cell cycle progression.3 Inappropriate over-expression of cdc25A has been
also reported in certain types of cancer.
Structurally 2 accommodates a tetrahydropyran-substituted 1,4-dihydroxy-2-pyridone skeleton. Recent
representatives of this family, sumbutoxin,4a,4b funiculosin,5 and oxysporidinone,6 possess a range of
biological activities. The absolute stereochemistry of 1, except for the C-17 carbon, was estimated to be 7R,
8R, and 10R by the N. O. E. experiment of 400MHz-1H-NMR analysis and a degradation study of TMC-69
(2) followed by application of the modified Mosher’s method.1a The unique structure and interesting
biological activities of TMC-69 derivatives prompted us to investigate a total synthesis of this class of
compounds to clarify the structure-bioactivity relationship (Scheme 1).

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HETEROCYCLES, Vol. 71, No. 3, 2007
10
17
8
OH
OH
7
O
O
H2, Pd-C
N
OH
O
hexahydro-TMC-69 (1)
17S; 1a
17R; 1b
N
OH
O
TMC-69 (2)
Scheme 1. Chemical structures of TMC-69 and TMC-69(6H)
RESULTS AND DISCUSSION
During our synthetic studies of 1,7a the total synthesis of (17S)-TMC-69(6H) (1a) and (17R)-TMC-69(6H)
(1b) was reported by Fürstner and coworkers using a Pd-catalyzed allyl-coupling method as a key step.7b,7c
However, the absoluteconfigurationof C-17 carbon was not clarified because of the almost similar spectral
characteristics of the two molecules. Therefore, we envisaged another approach to the (17S)-TMC-69(6H)
(1a) as a tentative synthetic target. Our synthetic strategy is outlined in Scheme 2. Thus, C3–C7 bonds of 1a
could be constructed by the Knoevenagel condensation of 4-hydroxy-5-phenyl-2-pyridone with pyranol
derivatives via a pyridinone methide intermediate followed by intramolecular conjugate addition.8 At this
stage, the thermodynamic conditions should lead the relative stereochemistry of C-7 and C-8 substituents
into a more thermodynamically favored trans configuration. Concerning the pyranol unit, we have recently
developed an efficient preparation of both enantiomers of 6-tert-butyldimethylsilyloxy-3-pyranones,
((R)-3, and (S)-3), in high e.e. via the lipase AK-catalyzed kinetic resolution,9 and planned to use the (S)
enantiomer as a precursor.
H3C
OH
H3C
O
CH3
R2
7
CH3
O
3
HO
N
OH
O
N
OR1
O
1a
Knoevenagel
condensation
OH
R2
O
+
HO
O
TBSO
O
N
O
OR
S-3
Scheme 2. Retrosynthetic analysis of 17S-(+) hexahydro-TMC-69
Starting from the pyranone ((S)-3), the trans-selective 1,4-addition of methyl-cuprate gave the ketone (4).
Subsequent Wittig olefination with known triphenylphosphonium salt 510 gave 6 as a mixture of isomers
(E:Z = ca. 1:2). Stereoselective hydrogenation of the olefinic moiety was accomplished with Ir-black as a
catalyst to give 7.11 Removal of the TBS group with tetra-n-butylammonium fluoride provided the pyranol

HETEROCYCLES, Vol. 71, No. 3, 2007
599
pyranol (8), the key intermediate for the subsequent condensation reaction (Scheme 3).
O
O
i
ii
TBSO
O
TBSO
O
S-3
4
99% ee
iii
RO
O
TBSO
O
7 : R =TBS
8 : R = H
E : Z = ca. 1 : 3
iv
6
Reagents and conditions: (i) MeLi, CuCN, TMSCl, THF (90%); (ii) n-BuLi,
+
(S)-CH3CH2(CH3)CH(CH2)4CH2PPh3 Br– (5) (95%); (iii) Ir-black, H2, dioxane (85%); (iv) TBAF, THF
(quant.).
Scheme 3
The pyridone unit was synthesized as follows. According to Snider’s procedure, pyridone (9) was
synthesized from phenylacetonitrile in three steps.12 Treatment with PhPOCl2, then oxidation with
m-CPBA, gave 2,4-dichloropyridine-N-oxide (10), which was treated with NaOMe to give 11.
Demethylation under acidic conditions, followed by monobenzylation, furnished the desired pyridone
(12)14 (Scheme 4).
Cl
OH
ref. 12
i, ii
CN
+
N
Cl
N
H
O
-
O
9
10
OH
OMe
iii
iv, v
+
N
O
N
OMe
OBn
-
O
12
11
Reagents and conditions: (i) PhPOCl2; (ii) m-CPBA, CH2Cl2 (80% 2 steps); (iii) NaOMe, MeOH (75%);
(iv) 47% HBr; (v) BnBr, K2CO3, DMF (54% 2 steps).
Scheme 4

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HETEROCYCLES, Vol. 71, No. 3, 2007
With both required units in hand, we then examined the crucial condensation step using various catalysts
and solvents. The best result was obtained when 12 was treated with two equivalents of 8 in the presence
of ethylenediammonium diacetate in methylene chloride at room temperature. Thus, condensation took
place cleanly, and the cyclized product (15) was obtained at a yield of 67% along with the stereoisomer
(14)13 (20%) via C-8 epimerization (Scheme 5). After separation of the undesired diastereomer (14), 15
was deprotected under hydrogenolytic conditions to give the desired (17S)-TMC-69(6H) (1a), which
showed good accordance with the analytical data of 1 derived from natural product (2) including optical
rotation.14 However, enantiomer of C17-epimer (ent-1b), synthesized by the same procedure starting from
(R)-3, showed almost same chemical shifts in the 300 MHz 1H-NMR analysis and similar optical rotation
with its mirror image.15 Next, we envisaged the comparison of 15 and 16 with semi-synthetic product (18),
which is derived via benzylation of authentic sample (1) (Scheme 6).16 However, again, neither the
comparison in the 400MHz 1H nor 13C-NMR analysis could find distinct differences between them. As a
result, determination of the absolute configuration of C-17 still remains a task for the future.
OH
O
i
HO
N
O
N
O
OBn
OBn
12
13
OH
OH
N
8
O
O
N
O
+
O
OR
OBn
14 (20%)
15; R = Bn (67%)
1a; R = H (quant.)
ii
1a; [α]D25= +146°
(1; [α]2D5= +142°)
Reagents and conditions: (i) 8, H2N(CH2)2NH2·2AcOH, CH2Cl2, 15 (67%), 14 (20%); (ii) Pd/C, H2
(quant.).
Scheme 5
OH
O
O
TBSO
O
N
O
S-3
OR
R = Bn: 16
R = H: ent-1b
OH
O
1
N
O
OBn
18
Scheme 6

HETEROCYCLES, Vol. 71, No. 3, 2007
601
In conclusion, we have established a convergent and efficient route to TMC-69 derivatives in a
stereo-controlled manner. Structure–activity relationship studies of TMC-69 derivatives using the route
described here and determination of the absolute stereochemistry of C-17 are under investigation and will
be reported elsewhere.
EXPERIMENTAL
General
Melting points were determined using a Büchi 535 melting point apparatus and are uncorrected. Optical
rotations were measured on a Horiba SEPA-200 high sensitive polarimeter. IR spectra were obtained
1
with a PerkinElmer Paragon 1000 FT-IR spectrophotometer. H-NMR spectra were measured with a
Varian Gemini-300 or a JEOL-LA400 spectrometer. Mass spectra were taken using a Finnigan MAT
SSQ7000C (APCI) or a JEOL JMS-HX 100 (FAB) mass spectrometer. Elemental analysis was
performed on a Perkin-Elmer 2400 or a Dionex-IC 320 elemental analyzer. All reactions were monitored
by TLC on silica gel 60 GF254 (Merck). Column chromatography was performed on Silica Gel 60N
(spherical, neutral) (100-210 µm, KANTO). Flash chromatography was performed on Silica Gel 60N
(spherical, neutral) (40-100 µm, KANTO). Recycling preparative HPLC was performed on LC-908
(Japan analytical industry Co., Ltd. JAIGEL-2H, CHCl3). In general, reactions were carried out in dry
solvents under argon atmosphere.
(5R,6S)-6-{[tert-Butyl(dimethyl)silyl]oxy}-5-methyldihydro-2H-pyran-3(4H)-one (4)
To a cooled (–78 °C) suspension of CuCN (1.08g, 12.1 mmol) in THF (10 mL) was added MeLi (1.14 M
in Et2O, 19.0 mL, 21.8 mmol), then the mixture was warmed up to 0 °C over 10 min. After stirring at
0 °C for 10 min, the reaction mixture was recooled to –78 °C and was added TMSCl (3.07 mL, 24.2
mmol) then a solution of (S)-(+)-6-tert-butyldimethylsilyloxy-2H-pyran-3(6H)-one (1.79 g, 7.84 mmol)
in THF (5 mL). After stirring at –78 °C for 10 min, the mixture was warmed up to 0 °C over 15 min and
stirred at 0 °C for 15 min. The reaction mixture was quenched with 2 N HCl (20 mL), diluted with Et2O,
and then filtered through a pad of Celite. The organic layer was separated and washed with H2O and sat.
aqueous NaHCO3, dried (MgSO4), and concentrated in vacuo. Purification of the residue by column
20
chromatography (10% AcOEt-hexane) gave 1.72 g (90%) of 4 as a colorless oil: [α]D = −131.8° (c =
0.710, CHCl3); 1H NMR (300 MHz, CDCl3) δ: 0.14 (s, 6H), 0.92 (s, 9H), 1.06 (d, 3H, J = 6.8 Hz), 2.14 (m,
1H), 2.23 (dd, 1H, J = 15.6, 7.5 Hz), 2.66 (dd, 1H, J = 15.7, 4.9 Hz), 3.87 (dd, 1H, J = 16.7, 0.7 Hz), 4.22
(dd, 1H, J = 16.7, 0.6 Hz), 4.93 (d, 1H, J = 4.2 Hz); IR (neat) 1732, 1472, 1463, 1253 cm-1; MS (APCI,
+AcONH4) m/z 294 (M+MeOH+NH4)+; Anal. Calcd for C12H24O3Si: C 58.97; H 9.90. Found: C 58.75; H
9.81.

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HETEROCYCLES, Vol. 71, No. 3, 2007
tert-Butyl(dimethyl)({(2S,3R)-3-methyl-5-[(6S)-6-methyloctylidene]tetrahydro-2H-pyran-2-yl}oxy)-
silane (6)
To a cooled (0 °C) suspension of ((S)-6-methyloctyl)triphenylphosphonium bromide10 (1.63 g, 3.47
mmol) in THF (20 mL) was added n-BuLi (1.6 M in hexane, 2.12 mL, 3.4 mmol). The reaction mixture
was stirred at 0 °C. After 30 min, resulting red suspension was cooled to –78 °C. To above mixture was
added a solution of (5R,6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-methyldihydro-2H-pyran-3(4H)-one (4)
(565 mg, 2.31 mmol) in THF (3 mL), and then allowed to warmed up to 0 °C over 30 min before stirring
at this temperature for 30 min. The reaction mixture was poured into ice-water and extracted with AcOEt.
The organic layer was washed with H2O and sat. aqueous NaCl, dried (MgSO4), and concentrated in
vacuo. Purification of the residue by column chromatography (50% CHCl3-hexane) gave 778 mg (95%)
1
of 6 as a colorless oil (E : Z = ca. 3:1 mixuture). H NMR (300 MHz, CDCl3) δ: 0.12 (d, 6H, 5.7 Hz),
0.80-0.95 (m, 18H), 1.05-1.35 (m, 9H), 1.60-1.74 (m 1H), 1.78-1.89 (m 1H), 1.92-2.20 (m, 2H), 2.47 (dd,
3/4H, J = 13.7, 4.4 Hz), 2.56 (dd, 1/4H, J = 14.3, 4.4 Hz), 3.83 (d, 1/4H, J = 12.8 Hz), 3.96 (d, 3/4H, J =
13.0 Hz), 4.22 (d, 1/4H, J = 11.9 Hz), 4.41 (d, 3/4H, J = 12.8 Hz), 4.55-4.58 (m, 1H), 5.15 (t, 3/4H, J =
7.5 Hz ), 5.27 (t, 1/4H, J = 7.5 Hz ).
tert-Butyl(dimethyl)({(2S,3R,5R)-3-methyl-5-[(6S)-6-methyloctyl]tetrahydro-2H-pyran-2-yl}oxy)-
silane (7)
To
a
mixture of tert-butyl(dimethyl)({(2S,3R)-3-methyl-5-[(6S)-6-methyloctylidene]-tetrahydro-
2H-pyran-2-yl}oxy)silane (6) (354 mg, 1.00 mmol) in dioxane (10 mL) was added Iridium-black (96 mg)
and hydrogenated under H2 atmosphere in an ordinary pressure and temperature. After 24 h, the catalyst
was removed by filtration and the filtrate was concentrated in vacuo. Purification of the residue by
20
column chromatography (9%-28% CH2Cl2-hexane) gave 302 mg (85%) of 7 as a colorless oil. [α]D
=
1
−37.05° (c = 0.448, CHCl3); H NMR (300 MHz, CDCl3) δ: 0.08 (s, 3H), 0.10 (s, 3H), 0.83 (d, 3H, J =
7.5 Hz), 0.85 (t, 3H, J = 8.4 Hz), 0.91 (s, 9H), 0.97 (d, 3H, J = 6.8 Hz), 1.00-1.38 (m, 14H), 1.58-1.74 (m,
3H), 3.46 (dd, 1H, J = 11.2, 2.9 Hz), 3.58 (dd, 1H, J = 11.0, 8.4 Hz), 4.57 (d, 1H, J = 3.5 Hz); IR (neat)
3425, 1361, 1331, 1252 cm-1; MS (APCI, +AcONH4) m/z 374 (M+NH4)+; Anal. Calcd for C21H44O2Si: C
70.72; H 12.43. Found: C 70.61; H 12.37.
(3R,5R)-3-Methyl-5-[(6S)-6-methyloctyl]tetrahydro-2H-pyran-2-ol (8)
To a cooled (0 °C) solution of tert-butyl(dimethyl)({(2S,3R,5R)-3-methyl-5-[(6S)-6-methyloctyl]-
tetrahydro-2H-pyran-2-yl}oxy)silane (7) (187 mg, 0.52 mmol) in THF (5 mL) was added
tetrabutylammonium fluoride (1.0 M in THF, 0.63 mL, 0.63 mmol), and the reaction mixture was allowed
to warmed up to rt. After stirring at rt for 2 h, the reaction mixture diluted with AcOEt, washed with H2O

HETEROCYCLES, Vol. 71, No. 3, 2007
603
and sat. aqueous NaCl. The organic layer was dried (MgSO4) and concentrated in vacuo. Obtained crude
material (126 mg) was used for the next conversion without further purification.
2,4-Dichloro-5-phenylpyridine 1-oxide (10)
Mixture of 4-hydroxy-5-phenylpyridin-2(1H)-one12 (9) (1.88 g, 10.0 mmol) and phenylphosphoric
dichloride (25 mL) was heated at 170 °C for 2 h. After cooled to rt, the reaction mixture was poured into
crashed-ice and afforded crystal was collected by filtration. Filtered solid was dissolved into AcOEt,
washed with sat. aqueous NaHCO3 and sat. aqueous NaCl. The organic layer was dried (Na2SO4) and
concentrated in vacuo to give crude dichloride 2.22 g as a colorless solid and used for the next conversion
without further purification. To a cooled (0 °C) solution of above dichloride (2.20 g, 9.82 mmol) in
CH2Cl2 (30 mL) was added m-chloroperbenzoic acid (72% purity, 4.84 g, 19.6 mmol). After 2 days,
additional m-chloroperbenzoic acid (72% purity, 4.84 g, 19.6 mmol) was added. After 20 h, to the
reaction mixture was added 10% Na2S2O3 and stirred at rt for 15 min. The reaction mixture was diluted
with CH2Cl2, washed with sat. aqueous NaHCO3 and sat. aqueous NaCl, dried (Na2SO4) and concentrated
in vacuo. The residual solid was recrystallized from CH2Cl2-Et2O to give 1.90 g, (80%, 2 steps) of 10 as a
colorless crystal.
mp 133-135 °C; 1H NMR (300 MHz, CDCl3) δ: 7.39-7.52 (m, 5H), 7.62 (s, 1H), 8.34 (s, 1H); IR (Nujol)
1351, 1313, 1279, 1251, 1220 cm-1; MS (APCI) m/z 240 (M+H)+; Anal. Calcd for C11H7NOCl2: C 55.03;
H 2.94; Cl 29.53; N 5.83. Found: C 54.85; H 2.88; Cl 29.55; N 5.93.
2,4-Dimethoxy-5-phenylpyridine 1-oxide (11)
To a 0.71 M NaOMe solution in MeOH (800 mL) [prepared from Na (13.2 g, 570 mmol) and MeOH (800
mL)], 2,4-dichloro-5-phenylpyridine 1-oxide (10) (19.2 g, 80 mmol) was added at 0 °C then stirred at rt.
After stirring at rt for 2 days, to above mixture was added 2 M HCl-MeOH (235 mL). Precipitated NaCl
was removed by filtration through a pad of Celite. The filtrate was concentrated in vacuo. Purification of
the residue by column chromatography (10-20% MeOH-CHCl3) then recrystallization from AcOEt gave
1
13.9 g (75%) of 11 as colorless crystals. mp 111-113 °C; H NMR (300 MHz, CDCl3) δ: 3.93 (s, 3H),
4.16 (s, 3H), 6.48 (s, 1H), 7.38-7.46 (m, 5H), 8.23 (s, 1H); IR (Nujol) 1669, 1621 cm-1; MS (APCI) m/z
232 (M+H)+; Anal. Calcd for C13H13NO3 2H2O: C 58.42; H 6.41; N 5.24. Found: C 58.32; H 6.27; N
5.37.
1-(Benzyloxy)-4-hydroxy-5-phenylpyridin-2(1H)-one (12)
The mixture of 2,4-dimethoxy-5-phenylpyridine 1-oxide (11) (12.0 g, 51.9 mmol) and 47% HBr (360
mL) was heated at reflux for 4 days. After cooled to rt, the reaction mixture was concentrated in vacuo

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HETEROCYCLES, Vol. 71, No. 3, 2007
and
the
residual
semisolid
was
triturated
with
H2O
to
give
crude
1-(hydoloxy)-4-hydroxy-5-phenylpyridin-2(1H)-one (8.95 g). as a colorless solid. To a solution of above
solid (4.0 g) in DMF (80 mL), was added K2CO3 (4.08 g, 29.6 mmol) and BnBr (2.30 mL, 19.7 mmol) at
rt. After stirring at rt for 12 h, the reaction mixture was quenched with H2O and extracted with AcOEt.
The organic layer was washed with H2O and sat. aqueous NaCl, dried (MgSO4) and concentrated in
vacuo. Purification of the residue by column chromatography (10% MeOH-CHCl3) gave 3.1 g (54%, 2
steps) of 12 as a colorless crystal. mp 252-255 °C; 1H NMR (300 MHz, DMSO-d6) δ: 5.18 (s, 2H), 5.88
(s, 1H), 7.27-7.53 (m, 5H), 7.69 (s, 1H), 11.03 (s, 1H); IR (Nujol) 3855, 3059, 1654, 1623, 1601, 1537
cm-1; MS (APCI) m/z 294 (M+H)+; Anal. Calcd for C18H15NO3: C 73.71; H 5.15; N 4.78. Found: C
73.25; H 5.22; N 4.75.
1-(Benzyloxy)-4-hydroxy-3-{(2R,3R,5R)-3-methyl-5-[(6S)-6-methyloctyl]tetrahydro-2H-pyran-2-yl}-
5-phenylpyridin-2(1H)-one
(15)
and
1-(benzyloxy)-4-hydroxy-3-{(2S,3S,5R)-3-methyl-5-
[(6S)-6-methyloctyl]tetrahydro-2H-pyran-2-yl}-5-phenylpyridin-2(1H)-one (14)
To a solution of 1-(benzyloxy)-4-hydroxy-5-phenylpyridin-2(1H)-one (12) (73.0 mg, 0.25 mmol) and
(3R,5R)-3-methyl-5-[(6S)-6-methyloctyl]tetrahydro-2H-pyran-2-ol (8) (121 mg, 0.50 mmol) in CH2Cl2
(5.0 mL) was added MS4A (powdered, 220 mg) and ethylenediammonium diacetate (45.0 mg, 0.25
mmol) at rt. After stirring at rt for 7 days, the reaction mixture was diluted with CH2Cl2 and filtered
through a pad of Celite. The filtrate was washed with H2O and sat. aqueous NaCl, dried (MgSO4), and
concentrated in vacuo. Purification of the residue by column chromatography (20-40% AcOEt-hexane)
gave 14 26.0 mg (20%; less polar) and 15 86.7 mg (67%; more polar) as a both colorless oil.
14: 1H NMR (300 MHz, CDCl3) δ: 0.83 (d, 3H, J = 7.2 Hz), 0.84-0.88 (m, 3H), 0.95 (d, 3H, J = 6.6 Hz),
1.00-1.38 (m, 14H), 1.60-1.78 (m, 1H), 1.85-1.99 (m, 2H), 3.21 (t, 1H, J = 11.4 Hz), 4.09 (m, 1H), 4.74
(d, 1H, J = 10.3 Hz), 5.21 (d, 1H, J = 10.8 Hz), 5.30 (d, 1H, J = 10.8 Hz), 7.04 (s, 1H), 7.18-7.45 (m,
10H), 9.52 (s, 1H); IR (Nujol) 3061, 1651, 1599 cm-1; MS (APCI) m/z 518 (M+H)+.
15: [α]D25 = +148.12° (c = 0.960, CHCl3); 1H NMR (300 MHz, CDCl3) δ: 0.83 (d, 3H, J = 7.3 Hz), 0.84 (t,
3H, J = 8.1 Hz), 0.91 (d, 3H, J = 6.8 Hz), 1.07-1.17 (m, 2H), 1.20-1.38 (m, 9H), 1.46-1.68 (m, 4H), 1.78
(d, 1H, J = 12.1 Hz), 2.08 (m, 1H), 3.76 (dd, 1H, J = 11.7, 2.6 Hz), 3.98 (d. 1H, J = 11.4 Hz) 4.77 (d, 1H,
J = 10.4 Hz), 5.21 (d, 1H, J = 10.8 Hz), 5.30 (d, 1H, J = 10.8 Hz), 7.02 (s, 1H), 7.18-7.45 (m, 10H), 9.54
(s, 1H); 13C-NMR (400MHz, CDCl3) δ:11.4, 18.1, 19.2, 27.1, 27.8, 29.5, 30.0, 30.9, 31.0, 34.0, 34.4, 36.2,
36.6, 72.5, 78.6, 81.7, 111.5, 113.1, 127.5, 128.3, 128.8, 129.1, 129.4, 130.3, 133.1, 133.9, 134.5, 158.1,
161.6; IR (Nujol) 3209, 1651, 1599 cm-1; MS (APCI) m/z 518 (M+H)+.

HETEROCYCLES, Vol. 71, No. 3, 2007
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1,4-Dihydroxy-3-{(2R,3R,5R)-3-methyl-5-[(6S)-6-methyloctyl]tetrahydro-2H-pyran-2-yl}-5-phenyl-
pyridin-2(1H)-one (1a)
To
a
mixture
of
1-(benzyloxy)-4-hydroxy-3-{(2R,3R,5R)-3-methyl-5-[(6S)-6-methyloctyl]-
tetrahydro-2H-pyran-2-yl}-5-phenylpyridin-2(1H)-one (15) (50.0 mg, 0.097 mmol) in dioxane (2 mL)
was added 10% Pd/C (20 mg) and hydrogenated in H2 atmosphere in an ordinary pressure and
temperature. After 1 h, the catalyst was removed by filtration through a pad of Celite and the filtrate was
concentrated in vacuo. Purification of the residue by recycling preparative HPLC gave 41.0 mg (quant.)
25
1
of desired compound as a colorless foam. [α]D = +146.12° (c = 0.516, MeOH); H NMR (300 MHz,
CDCl3) δ: 0.77 (d, 3H, J = 6.6 Hz), 0.82-0.87 (m, 6H), 1.00-1.16 (m, 2H), 1.18-1.38 (m, 9H), 1.40-1.64
(m, 4H), 1.76 (d, 1H, J = 11.9 Hz), 2.06 (m, 1H), 3.72 (dd, 1H, J = 11.5, 2.6 Hz), 3.96 (d, 1H, J = 11.4
Hz), 4.68 (d, 1H, J = 10.4 Hz), 7.32-7.49 (m, 5H), 7.67 (s, 1H), 9.55 (s, 1H); IR (Nujol) 3178, 3109, 2599,
1641 cm-1; MS (APCI) m/z 428 (M+H)+.
1,4-Dihydroxy-3-{(2S,3S,5S)-3-methyl-5-[(6S)-6-methyloctyl]tetrahydro-2H-pyran-2-yl}-5-phenyl-
pyridin-2(1H)-one (ent-1b)
ent-1b was prepared by the same procedure as above described manners starting from (R)-3
[α]D25= –139.62° (c = 0.265, MeOH); 1H NMR (300 MHz, CDCl3) δ: 0.79 (d, 3H, J = 6.6 Hz), 0.82-0.87
(m, 6H), 1.00-1.16 (m, 2H), 1.18-1.38 (m, 9H), 1.40-1.64 (m, 4H), 1.76 (d, 1H, J = 12.1 Hz), 2.06 (m,
1H), 3.72 (dd, 1H, J = 11.5, 2.6 Hz), 3.96 (d, 1H, J = 11.4 Hz), 4.68 (d, 1H, J = 10.6 Hz), 7.32-7.49 (m,
5H), 7.67 (s, 1H), 9.52 (s, 1H); IR (Nujol) 3182, 1641, 1580, 1554, 1498 cm-1; MS (APCI) m/z 428
(M+H)+
REFERENCES AND NOTES
1. a) J. Kohno, N. Hirano, K. Sugawara, M. Nishio, T. Hashiyama, K. Kawano, N. Nakanishi, and S.
Komatsubara, Tetrahedron, 2001, 57, 1731. b) N. Hirano, J. Kohno, K. Kawano, M. Nishio, T.
Okuda, N. Nakanishi, and S. Komatsubara, J. Antibiot., 2001, 54, 421.
2. Contrast to the reported data sited in ref. 1b), TMC-69-6H showed weak inhibitory activities towards
cdc25A and cdc25B in the ref. 7b).
3. I. Nilsson and I. Hoffmann, Progress in Cell Cycle Research, 2000, 4, 107, and literature cited
therein.
4. a) J. -C. Kim and Y. W. Lee, Appl. Environ. Microbiol. 1994, 60, 4380. b) J. -C. Kim, Y. W. Lee, H.
T. Tamura, and T. Yoshizawa, T. Tetrahedron Lett., 1995, 36, 1047.
5. K. Ando, I. Matsuura, Y. Nawata, H. Endo, H. Sasaki, T. Okytomi, T. Saehi, and G. Tamura, J.

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HETEROCYCLES, Vol. 71, No. 3, 2007
Antibiot., 1978, 31, 533.
6. J. Breinholt, S. Ludvigsen, B. R. Rassing, C. N. Rosendahl, S. E. Nielsen, and C. E. Olsen, J. Nat.
Prod., 1997, 60, 33.
7. Synthetic studies for the TMC-69-6H, a) K. Sugawara, J. Kohno, N. Nakanishi, and T. Hashiyama,
Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 2000, 42, 661. b) A. Fürstner, F. Feyen, H. Prinz,
and H. Waldmann, Angew. Chem. Int. Ed., 2003, 42, 5361. c) A. Fürstner, F. Feyen, H. Prinz, and H.
Waldmann, Tetrahedron, 2004, 60, 9543.
8. Examples of pyridinone methide as reactive intermediates; a) N. N. Girotra and N. L. Wendler,
Heterocycles, 1978, 9, 417. b) L. F. Titze, S. Brands, T. Brumby, and J. Fennen, Angew. Chem., Int.
Ed. Engl., 1990, 29, 665. c) D. R. Williams and R. A. Turske, Org. Lett., 2000, 20, 3217. d) J.
Findlay, J. Krepinsky, F. Y. Shum, and W. H. Tam, Can. J. Chem., 1976, 54, 270. See also ref. 13
9. K. Sugawara, Y. Imanishi, and T. Hashiyama, Tetrahedron: Asymmetry, 2000, 11, 4529.
10. Synthesis of both the enantiomers of (6-methyloctyl)triphenylphosphonium bromide see, H. G.
Bestmann, R. T. S. Frighetto, N. Frighetto, and O. Vostrowsky, Liebigs Ann. Chem., 1990, 829.
11. When Pd/C was used instead of Ir-black, stereoselectivity decreased and an epimer was formed (ca.
10%).
12. B. B. Snider and Q. Lu, J. Org. Chem., 1996, 61, 2839.
13. Comparisons of coupling constants of 15 and 14 in 1H NMR (400 MHz, CDCl3): 15: J H7, H8, = 10.5
Hz, J H10, H11ax, = 2.7 Hz, J H10, H11eq, = 1.0 Hz, 14: J H7, H8, = 10.3 Hz, J H10, H11ax, = 11.2 Hz, J
H10,
H11eq, = 1.7 Hz. and NOE analysis of 15 (see below) are in full accordance with the depicted
configuration shown in Scheme 5.
H
H
H
8
H
9
Me
Ar
H
H
O
NOE
7
11
H
H
H
Representative observed NOE of 15
25
14. The optical rotation of 1a, [α]D = +146.12° (c = 0.516, MeOH), showed higher value compared
20
with the reported data in the reference 7c, [α]D = +88.6° (c = 0.95, MeOH). The reason for this
discrepancy is not clear, but purity of 1a may differ. According to the experimental section in the
literature, it apparently does not include purification step after final N-hydroxylation reaction.
15. According to ref. 7b) 1a and its C-17 epimer, (1b) had almost the same analytical properties in 600
MHz 1H and 13C-NMR analysis
16. 18 was synthesized as follows: To a cooled (0 °C) solution of 1 (ref. 1a, 100 mg, 0.234 mmol) in

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DMF (2 mL), NaH was added (60% in oil, 9.0 mg, 0.225 mmol) and then allowed to warm up to rt,
before adding benzyl bromide (0.028 mL, 0.235 mmol). The solution was then stirred at rt for 15 h.
The reaction mixture was poured into crushed-ice and extracted with AcOEt. The organic layer was
separated and washed with H2O, sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo.
Purification of the residue by column chromatography (33–66% AcOEt-hexane) gave 114 mg of 18
(94%) as colorless oil.