Synthetic study on telomerase inhibitor, D8646-2-6: Synthesis of the key intermediate using Sn(OTf)2 or Sc(OTf)3 mediated aldol-type reaction and stille coupling

Article abstract of DOI:10.1248/cpb.55.495

The synthesis of the key intermediate (4) in the proposed route to D8646-2-6 is described. The aldol reaction of the carbohydrate-containing pyrone 7 with the aldehyde 6 was accomplished by using LiHMDS and Sc(OTf)₃ or Sn(OTf)₂. The

Full text of DOI:10.1248/cpb.55.495

March 2007
Notes
Chem. Pharm. Bull. 55(3) 495—499 (2007)
495
Synthetic Study on Telomerase Inhibitor, D8646-2-6: Synthesis of the Key
Intermediate Using Sn(OTf)2 or Sc(OTf)3 Mediated Aldol-Type Reaction
and Stille Coupling
Akira KANAI,a Yoshifumi TAKEDA,a Kouji KURAMOCHI,b Atsuo NAKAZAKI,a and Susumu KOBAYASHI*,a
a Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI); and b Department of Applied Biological
Science, Faculty of Science and Technology, Tokyo University of Science (RIKADAI); 2641 Yamazaki, Noda, Chiba
278–8510, Japan. Received December 12, 2006; accepted December 19, 2006; published online December 22, 2006
The synthesis of the key intermediate (4) in the proposed route to D8646-2-6 is described. The aldol reaction
of the carbohydrate-containing pyrone 7 with the aldehyde 6 was accomplished by using LiHMDS and Sc(OTf)3
or Sn(OTf)2. The stepwise dehydration reaction of the aldol adduct 14, followed by Stille coupling with vinyl
stannane 5 which contained phosphonate gave the desired 4.
Key words aldol-type reaction; carbohydrate-containing pyrone; stille coupling; scandium triflate; tin triflate; vinyl stannane
which contains phosphonate
In 2002, the Mitsubishi Pharma group reported the isola- tion of pyrones,12—24) the application of this approach to a
tion of a telomerse inhibitor, D8646-2-6 (1) from the culture carbohydrate-containing compound is unprecedented. Since
broth of fungus Epicoccum purpurascens.1) The compound oxygenated functionalities of substrates might influence on
has a unique C3-pyranosyl 4-hydroxypyrone moiety2) and the reactivity of carbanion, the reactivity of such carbo-
conjugated polyene unit.3—7) However the structure of 1 in- hyrare-bearing pyrones as well as its synthetic utilities is
cluding the relative and absolute stereochemistry has not quite interesting. Herein, we report the synthesis of the key
been fully elucidated yet. The potent biological activity and intermediate 4 using aldol-type reaction of carbohydrate con-
structural complexity of this compound prompted us to initi- taining pyrone 7 followed by stepwise dehydration and Stille
ate synthetic studies toward 1. In our preceding paper, we coupling with vinyl stannane 5 which contains phosphonate
have reported the construction of the C-glycosyl 4-hydroxy group.
pyrone moiety of 1. Comparison of the NMR spectra of the
The feasibility of the key aldol-type reaction was evalu-
C3-galactopyranosyl 4-hydroxy-2-pyrone moiety 2 with those ated through model systems. The aldol-type reaction of
of natural 1, demonstrated that the carbohydrate moiety of 725—27) with (2E,4E)-hexa-2,4-dienal by the simple treatment
the latter compound to be C3-galactopyranoside (Fig. 1).8)
with LiHMDS to give 8 in only 6% yield and 62% of 7 was
Our synthetic strategy toward the total synthesis of 1 is recovered (Chart 2).
shown in Chart 1. Due to the labile nature of the polyeninc
However, the aldol-type reaction of 4-methoxy-6-methyl-
side chain, our synthestic strategy involved an initial aldol 2-pyrone 9 with (2E,4E)-hexa-2,4-dienal proceeded smooth-
condensation of the pyrone moiety with the side chain unit ly under the same conditions to afford the aldol product 10 in
(C8—C12), followed by the elongation of the remaining side 87% yield. These results indicated that the carbohydrate moi-
chain unit. Since the stereochemistry at C21 and C23 was not ety greatly influenced the aldol-type reaction. We reasoned
determined, we envisaged that phosphonate 4 would serve as that the highly oxygenated functional group of 7 might de-
a versatile key intermediate for the synthesis of D8646-2-6 crease the reactivity of the pyrone-stabilized carbanion
and its stereoisomeres. Horner–Wadsworth–Emmons reac- through the coordination to the lithium ion or by steric
tion was successfully utilized by Cha and co-workers in the
total synthesis of citreoviridin9) which contains polyene con-
jugated with pyrone ring. Phosphonate 4 could be synthe-
sized by Stille coupling10) of triene 15 with vinyl stannane
which contains phosphonate.11) Although there have been
some reports concerning the aldol-type reaction and alkyla-
Fig. 1. Structure of D8646-2-6 and C3-Pyranosyl 4-Hydroxy-2-pyrone
Moiety
Chart 1. Synthetic Strategy of D8646-2-6
© 2007 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: kobayash@rs.noda.tus.ac.jp

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Vol. 55, No. 3
Table 2. Dehydration of Aldol Adduct 8
Yield
(%)
Entry
Conditions
1
2
3
4
5
CCl3COCl, Et3N/CH2Cl2, 0 °C, 0.5 h
TFAA, Et3N/CH2Cl2, 0 °C, 0.5 h
Tf2O/CH2Cl2, 0 °C, 10 min
57
29
55
21
Chart 2. The Aldol Reaction of Pyrone 7 and Pyrone 9 with (2E,4E)-
Hexa-2,4-dienal
HfCl4(THF)2/THF, 0 °C, 3 h
Ac2O, Py, DMAP/CH2Cl2, 2 h then DBU/CH2Cl2, 0 °C, 3 h 74
Table 1. Aldol-Type Reaction of Pyrone Moiety 7 with (2E,4E)-Hexa-2,4-
dienal
Yield (%)
LiHMDS
(eq)
Additive
(1.0 eq)
Entry
8
11
1
2
3
4
5
6
7
8
9
1
1
3
1
3
1
3
1
1
3
LiCl
Me2AlCl
Me2AlCl
TiCl(Oi-Pr)3
TiCl(Oi-Pr)3
Sc(OTf)3
Sc(OTf)3
SnCl4
0
9
Trace
15
0
22
29
20
7
Chart 3. Dehydration of Aldol Adduct 8 with Trichloroacetylchloride, and
Plausible Mechanism of the Rearrangement
35
26
45
0
6
54
9
With the aldol adduct 8 in hand, direct dehydration was
next investigated. When the aldol adduct 8 was subjected to a
conventional dehydration conditions using CCl3COCl and
Et3N,28) the desired triene 11 was obtained in 57% yield as a
2 : 1 mixture of E and Z isomers, in addition to alcohol 12
(10%) and trichloroacetate 13 (4%) (Table 2, entry 1 and
Chart 3).29)
Sn(OTf)2
Sn(OTf)2
4
69
37
3
10
hidrance.
We next examined a variety of additives in the above
The formation of alcohol 12 and trichloroacetate 13 might
aldol-type reaction (Table 1). The addition of LiCl did not af- be explained by the rearrangement shown in Chart 3. Similar
fect the yield of the aldol products 8 and 11 (entry 1). How- sigmatropic rearrangement of allylic trichloroacetimidate
ever, the addition of Me2AlCl, TiCl(OiPr)3, Sc(OTf)3, SnCl4 was also reported by Overman.30,31) We also examined other
or Sn(OTf)2, improved the yield of the products (entries 2, 4, direct dehydration methods such as TFAA–Et3N, Tf2O and
6, 8, 9). When Me2AlCl or TiCl(OiPr)3 was used, the major HfCl4(thf)232) to afford the triene 11 in low to moderate yield
product was 8 (entries 2, 4). On the other hand, the dehy- (Table 2, entries 2—4). Finally we found that the stepwise
drated product 11 was obtained as a major product using method involving an initial acetylation (Ac2O–pyridine,
Sc(OTf)3 or Sn(OTf)2 as an additive (entries 6, 9). The addi- DMAP) followed by elimination with DBU afforded the best
tion of SnCl4 slightly improved the yield of the aldol prod- result (74%) (entry 5).
ucts with almost 1:1 ratio of 8 and 11 (entry 8). Using 3 eq of
The present Sc(OTf)3 or Sn(OTf)2 mediated aldol-type
LiHMDS, no significant improvement was achieved with reaction was successfully applied to the synthesis of the
Me2AlCl or TiCl(Oi-Pr)3 as an additive (entries 3, 5). How- key intermediate of D8646-2-6. Pyrone 7 was reacted with
ever, we found that the aldol-type reaction proceeded (2E,4E)-5-bromopenta-2,4-dienal 633,34) using LiHMDS and
smoothly when LiHMDS (3 eq) and Sc(OTf)3 or Sn(OTf)2 Sc(OTf)3 or Sn(OTf)2 to give the aldol product 14 in 85% or
(1 eq) were used in the reaction (entries 7, 10).
83% yield, respectively (Chart 4). It should be emphasized
We tentatively speculate that scandium(III) and tin(II) that no reaction occurred without Sn(OTf)2 or Sc(OTf)3.
might coordinate to both carbonyl oxygen of the aldehyde Aldol adduct 14 was then subjected to a stepwise elimination
(activation of an electrophile) and ether oxygen of galactose described above (Ac2O, pyridine and DMAP, then DBU;
moiety (proximity effect). We also believe that Sc(OTf)3 or 78%35)) to obtain the triene 15 with complete stereoselectiv-
Sn(OTf)2 stabilize the alkoxide derivative of the aldol-type ity.
product by the formation of the stable scandium(III) or tin(II)
alkoxide.
With the triene 15 in hand, we next examined Stille cou-
pling of 15 with vinyl stannane 5 which is bearing phospho-

March 2007
497
spectrometer (API QSTAR pulsar i) under conditions as High resolution,
using poly(ethylene glycol) as internal standard.
4-Benzyloxy-6-methyl-3-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-benzyl-b-D-galactopyra-
nosyl)-2-pyrone (7) To a stirred solution of C3-galactopyranosyl 4-hy-
droxy-2-pyrone (10.13 g, 15.6 mmol), BnOH (2.5 ml, 24.1 mmol), and PPh3
(5.3 g, 20.1 mmol) in dry THF (50 ml) under argon was added DIAD
(11.0 ml, 40% solution in toluene, 24.1 mmol) at room temperature. After
stirred for 2 h, the reaction mixture was evaporated in vacuo. The residue
was purified by flash chromatography (silica gel, 2 : 1 hexane/EtOAc) to af-
ford corresponding benzyl ether (7) (9.9 g, 86%) as colorless foam.
Rf 0.38 (1 : 1 hexane–EtOAc). [a]D24 ꢀ48.2° (cꢁ0.38, CHCl3). IR (neat)
cmꢀ1: 2873, 1702, 1645, 1561, 1453, 1215, 1090, 756. 1H-NMR (600 MHz,
DMSO-d6, mixture of rotamers): d 2.19 (1.5H, s), 2.20 (1.5H, s), 3.45—3.56
(2H, m), 3.67—3.75 (2H, m), 4.06 (1H, dd, Jꢁ2.4, 9.5 Hz), 4.24 (0.5H, d,
Jꢁ9.9 Hz), 4.38—4.41 (1.5H, m), 4.44—4.49 (2H, m), 4.54—4.57 (1.5H,
m), 4.59 (0.5H, d, Jꢁ12.1 Hz), 4.65 (0.5H, d, Jꢁ11.9 Hz), 4.65 (0.5H, d, Jꢁ
12.1 Hz), 4.74 (0.5H, d, Jꢁ10.9 Hz), 4.76 (0.5H, d, Jꢁ11.0 Hz), 4.78 (0.5H,
d, Jꢁ12.1 Hz), 4.78 (0.5H, d, Jꢁ11.9 Hz), 4.84 (0.5H, d, Jꢁ12.1 Hz), 4.85
(0.5H, d, Jꢁ11.8 Hz), 5.07 (0.5H, d, Jꢁ13.1 Hz), 5.22 (0.5H, d, Jꢁ13.1 Hz),
5.27 (0.5H, d, Jꢁ12.8 Hz), 5.32 (0.5H, d, Jꢁ12.8 Hz), 6.51 (0.5H, S), 6.53
(0.5H, S), 7.00—7.43 (25H, m). 13C-NMR (100 MHz, DMSO-d6, mixture of
rotamers): d 19.9, 20.0, 69.3, 70.1, 70.6, 71.3, 72.1, 72.5, 72.6, 73.7, 73.9,
74.0, 74.0, 74.5, 74.6, 75.0, 75.7, 76.9, 77.1, 84.4, 84.5, 96.1, 96.5, 100.9,
101.2, 127.1, 127.1, 127.2, 127.3, 127.4, 127.5, 127.6, 127.6, 127.7, 127.8,
127.9, 128.1, 128.1, 128.1, 128.2, 128.3, 128.3, 128.4, 128.7, 135.9, 136.0,
138.3, 138.9, 139.0, 139.0, 139.3, 139.3, 139.4, 161.7, 163.3, 164.2, 164.5,
168.2, 168.8. HR-ESI-MS m/z: Calcd for C47H46O8Na ([MꢂNa]ꢂ) 761.3084,
Found 761.3089.
Chart 4. Application of the Methodology for the Preparation of the Triene
15
Aldol Condensation of Pyrone Moiety 7 with 2E,4E-Hexa-2,4-dienal.
Sn(OTf)2 Mediated Aldol Reaction To a stirred solution of pyrone moi-
ety 7 (2.0 g, 3.00 mmol) in dry THF (30 ml) at ꢀ78 °C under argon was
dropwise added LiHMDS (9.0 ml, 1.0 M solution in THF, 9.00 mmol). After
being stirred for 30 min, 2E,4E-hexa-2,4-dienal (0.7 ml, 6.0 mmol) and
Sn(OTf)2 (1.2 g, 2.8 mmol) was added successively at ꢀ78 °C. After the re-
action mixture was stirred for additional 2.5 h, it was allowed to warm up to
the room temperature. Then it was poured into saturated aqueous NH4Cl.
After the mixture was filtered through Celite®, the product was extracted
with EtOAc. The organic phase was washed with 1 N HCl, and it was neu-
tralized with saturated aqueous NaHCO3. The organic extract was washed
with Brine, dried with Na2SO4, then filtered, and evaporated in vacuo. The
residue was purified by flash chromatography (silica gel, 2 : 1 benzene/Et2O)
to afford aldol adduct 8 (1.48 g, 69%) as a pearl yellow foam and triene 11
(0.09 g, 3%) as a yellow foam.
Sc(OTf)3 mediated aldol reaction was carried out with the same procedure
described above to afford aldol adduct 8 (54%) and triene 11 (20%).
(1E,3E,5E)-1-{4-Benzyloxy-3-(2,3,4,6,-tetra-O-benzyl-b-D-galactopy-
ranosyl)-2-pyrone}-1,3,5-heptatriene (11) To a stirred solution of aldol
adduct 8 (0.46 g, 0.55 mmol) in dry CH2Cl2 (6 ml) at room temperature
under argon was added acetic anhydride (0.26 ml, 2.75 mmol), pyridine
(0.23 ml, 2.75 mmol), and 4-dimethylamino pyridine (0.007 g, 0.05 mmol).
After being stirred for 2 h, the reaction medium was poured into saturated
Chart 5. Stille Coupling of Triene 15 with Vinyl Stannane 5 which Con-
tains Phosphonate
nate (Chart 5). Although the Stille coupling of 15 with vinyl
stannane 5 did not proceed in the presence of Pd(PPh3)4 as
catalyst precursor, desired coupling product 4 was obtained
in 42% yield and reductive product 16 in 12% yield in the
presence of Pd2(dba)3. When AsPh3 was added in the reac-
tion mixture, the coupling product was obtained in 63% yield
without accompanying an undesired 16.
In conclusion, we found that the aldol-type reaction of car-
bohydrate-bearing pyrone with aldehyde proceeded by the
addition of Sn(OTf)2 or Sc(OTf)3. Using a combination of
this methodology, followed by stepwise dehydration reaction aqueous NH4Cl and the product was extracted with CH2Cl2 (100 ml). The
organic extract was washed with Brine, dried with Na2SO4, then filtered, and
evaporated in vacuo. The residue was through short plug of silica gel to re-
move pyridine and evaporated in vacuo. The crude product was used in the
next step without further purification.
and stille coupling, we were able to achieve the synthesis of a
key intermediate 4. Further investigation toward the total
synthesis of D8646-2-6 (1) is currently in progress.
To a cold (0 °C) solution of crude product in 50 ml of CH2Cl2 was added
Experimental
DBU (0.12 ml, 0.83 mmol). After being stirred for 3 h, the reaction medium
All moisture-sensitive reactions were carried out under an atmosphere of was poured into saturated aqueous NH4Cl and the product was extracted
argon in oven-dried glassware and the solvents were freshly distilled. All re- with CH2Cl2 (150 ml). The organic extract was washed with Brine, dried
actions were monitored by TLC, which was carried out on 0.25 mm Silica with Na2SO4, then filtered, and evaporated in vacuo. The residue was puri-
Gel 60 F254 plates (E. Merck) and spots were visualized with UV light. Col- fied by flash chromatography (silica gel, 4 : 1 hexane/EtOAc) to afford triene
umn chromatography utilized PSQ 100B (Fuji Silysia Co., Ltd., Japan). The
11 (0.33 g, 74% over 2 steps) as a yellow foam.
1
NMR spectra (1H, 13C, two-dimensional H–1H COSY, HMQC, HMBC and
The stereochemistry of compound 11 was determined by 1H-NMR analy-
NOESY) were obtained on a Bruker 600 MHz spectrometer (Avance DRX- sis in DMSO-d6 at 100 °C.
600) or Bruker 400 MHz spectrometer (Avance DRX-400), using CDCl3 so-
Rf 0.46 (2 : 1 hexane–EtOAc). [a]D24 ꢀ10.8°(cꢁ0.35, CHCl3). IR (neat)
lutions, unless otherwise noted. Chemical shifts for 1H-NMR were expressed cmꢀ1: 2927, 1701, 1636, 1540, 1097. 1H-NMR (600 MHz, DMSO-d6, mix-
in parts per million (ppm) downfield from tetramethylsilane (d) in duteri- ture of rotamers): d 1.79—1.83 (3H, m), 3.48—3.58 (2H, m), 3.69—3.76
ochloroform as internal standard or in ppm relative to the centerline of a (2H, m), 4.07—4.08 (1H, m), 4.26 (0.5H, d, Jꢁ11.6 Hz), 4.40 (0.5H, d, Jꢁ
quintet at 2.54 ppm for dimethylsulfoxide in duteriodimethylsulfoxide and 11.9 Hz), 4.41 (0.5H, d, Jꢁ11.9 Hz), 4.43 (0.5H, d, Jꢁ11.7 Hz), 4.47—4.51
coupling constants (J) are in hertz (Hz). Optical rotations were recorded (2H, m), 4.57—4.60 (1.5H, m), 4.60 (0.5H, d, Jꢁ12.1 Hz), 4.66 (0.5H, d,
using CHCl3 or MeOH as solvents on a JASCO P-1030 digital polarimeter. Jꢁ11.9 Hz), 4.67 (0.5H, d, Jꢁ12.1 Hz), 4.75—4.80 (1.5H, m), 4.80 (0.5H,
IR spectra were recorded on a JASCO FT/IR-410 spectrometer using NaCl d, Jꢁ12.0 Hz), 4.85 (0.5H, d, Jꢁ12.1 Hz), 4.87 (0.5H, d, Jꢁ12.1 Hz), 5.10
plate (neat). Mass spectra were recorded on an Applied Biosystems mass
(0.5H, d, Jꢁ13.1 Hz), 5.24 (0.5H, d, Jꢁ13.1 Hz), 5.30 (0.5H, d, Jꢁ12.7 Hz),

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Vol. 55, No. 3
providing Sn(OTf)2.
5.35 (0.5H, d, Jꢁ12.7 Hz), 5.92—5.97 (1H, m), 6.20—6.26 (1H, m), 6.27
(0.5H, d, Jꢁ15.2 Hz), 6.28 (0.5H, d, Jꢁ15.4 Hz), 6.32—6.37 (1H, m),
6.63—6.67 (1H, m), 6.64 (0.5H, s), 6.66 (0.5H, s), 7.01—7.45 (26H, m).
13C-NMR (100 MHz, CDCl3, mixture of rotamers): d 18.6, 68.7, 69.1, 70.3,
70.8, 72.3, 72.5, 72.8, 73.4, 73.8, 74.0, 74.2, 74.4, 74.6, 75.0, 75.5, 75.7,
77.2, 77.6, 85.3, 85.5, 95.7, 96.4, 102.9, 103.6, 120.9, 126.6, 127.1, 127.4,
127.4, 127.5, 127.5, 127.6, 127.7, 127.9, 127.9, 128.0, 128.1, 128.3, 128.4,
128.5, 128.8, 131.4, 134.4, 135.3, 135.3, 137.1, 137.3, 138.0, 138.0, 138.7,
139.0, 139.2, 139.3, 139.5, 139.5, 139.6, 159.3, 160.3, 161.5, 164.3, 167.6,
168.3. HR-ESI-MS m/z: Calcd for C53H52O8Na ([MꢂNa]ꢂ) 839.3554,
Found 839.3524.
References and Notes
1) Kimura J., Furui M., Kanda M., Sugiyama M., Jpn. Kokai Tokkyo
Koho, JP 2002047281 (2002).
2) Review of natural products containing pyrone ring, see: McGlacken G.
P., Fairlamb Ian J. S., Nat. Prod. Rep., 22, 369—385 (2005).
3) Recent report for natural products containing conjugated polyene see:
Wang F., Luo D.-Q., Liu J.-K., J. Antibiot., 58, 412—415 (2005).
4) Recent report for natural products containing conjugated polyene see:
Igarashi Y., In Y., Ishida T., Fujita T., Yamanaka T., Onaka H., Furumai
T., J. Antibiot., 58, 523—525 (2005).
5) Recent report for natural products containing conjugated polyene see:
Weber R. W. S., Muci A., Davoli P., Tetrahedron Lett., 45, 1075—1078
(2004).
6) Review for natural products containing polyene, see: Ishibashi M.,
Med. Chem., 1, 575—590 (2005).
7) Review for natural products containing polyene, see: Thirsk C., Whit-
ing A., J. Chem. Soc., Perkin Trans. 1, 2002, 999—1023 (2002).
8) Kanai A., Kamino T., Kuramochi K., Kobayashi S., Org. Lett., 5,
2837—2839 (2003).
9) Wang K., Venkataraman H., Kim Y. G., Cha J. K., J. Org. Chem., 56,
7174—7177 (1991).
10) Scott W. J., “The Stille Reaction in Organic Reactions,” Vol. 50, Chap.
1, ed. by Paquette L. A., John Willey & Sons, Inc., New York, 1997,
pp. 1—652.
11) Smith A. B., III, Wan Z., J. Org. Chem., 65, 3738—3753 (2000).
12) For the aldol reaction of pyrone, see: Kirsch S. F., Bach T., Chem. Eur.
J., 11, 7007—7023 (2005).
13) For the aldol reaction of pyrone, see: Casiraghi G., Zanardi F., Ap-
pendino G., Rassu G., Chem. Rev., 100, 1929—1972 (2000), and refer-
ences therein.
(1E,3E,5E)-6-Bromo-1-{4-benzyloxy-3-(2,3,4,6,-tetra-O-benzyl-a-D-
galactopyranosyl)-2-pyrone}-1,3,5-hexatriene (15) The aldol reaction of
pyrone moiety 7 with aldehyde 6 was carried out with the same procedure
described above.
The stereochemistry of compound 15 was determined by 1H-NMR analy-
sis in DMSO-d6 at 100 °C.
Rf 0.4 (15 : 1 benzene–CH3CN). [a]D24 ꢀ5.1° (cꢁ1.38, CHCl3); IR (neat)
1
cmꢀ1: 3060, 3029, 2869, 1701, 1536, 1357, 1098, 997, 744, 699. H-NMR
(600 MHz, DMSO-d6, mixture of rotamers): d 3.45—3.56 (2H, m), 3.68—
3.74 (2H, m), 4.06 (1H, m), 4.25 (0.5H, d, Jꢁ11.6 Hz), 4.37—4.50 (4H, m),
4.55—4.60 (2H, m), 4.65 (0.5H, d, Jꢁ12.2 Hz), 4.65 (0.5H, d, Jꢁ12.2 Hz),
4.73—4.79 (2H, m), 4.84 (0.5H, d, Jꢁ12.9 Hz), 4.87 (0.5H, d, Jꢁ12.7 Hz),
5.09 (0.5H, d, Jꢁ13.1 Hz), 5.22 (0.5H, d, Jꢁ13.1 Hz), 5.28(0.5H, d, Jꢁ
12.7 Hz), 5.33 (0.5H, d, Jꢁ12.7 Hz), 6.37 (0.5H, d, Jꢁ15.3 Hz), 6.38 (0.5H,
d, Jꢁ15.3 Hz), 6.53 (0.5H, dd, Jꢁ11.0, 14.9 Hz), 6.54 (0.5H, dd, Jꢁ10.9,
14.8 Hz), 6.62 (1H, dd, Jꢁ10.8, 14.8 Hz), 6.70 (0.5H, s), 6.71 (0.5H, s), 6.85
(0.5H, d, Jꢁ13.4 Hz), 6.86 (0.5H, d, Jꢁ13.4 Hz), 6.95 (0.5H, dd, Jꢁ10.8,
13.4 Hz), 6.96 (0.5H, dd, Jꢁ10.6, 13.3 Hz), 6.99—7.43 (26H, m). 13C-NMR
(100 MHz, DMSO-d6, mixture of rotamers): d 69.3, 70.2, 70.7, 71.3, 72.1,
72.5, 72.6, 73.1, 73.9, 74.0, 74.1, 74.5, 74.6, 75.0, 75.7, 76.9, 77.1, 84.3,
84.5, 97.7, 98.2, 102.9, 103.2, 113.3, 113.4, 124.0, 127.2, 127.2, 127.3,
127.3, 127.4, 127.4, 127.5, 127.5, 127.6, 127.6, 127.7, 127.9, 127.9, 128.1,
128.1, 128.1, 128.2, 128.3, 128.4, 128.4, 128.7, 132.2, 132.3, 135.0, 135.2,
135.5, 135.6, 135.8, 136.0, 137.5, 138.3, 138.9, 139.0, 139.0, 139.2, 139.3,
139.4, 158.5, 159.3, 160.6, 163.4, 167.8, 168.3. HR-ESI-MS m/z: Calcd for
C52H49O8NaBr ([MꢂNa]ꢂ) 903.2508, Found 903.2509.
14) For the aldol reaction of pyrone, see: Oikawa H., Kobayashi T.,
Katayama K., Suzuki Y., Ichihara A., J. Org. Chem., 63, 8748—8756
(1998).
15) For the aldol reaction of pyrone, see: Lyga J. W., J. Heterocyclic
Chem., 32, 515—518 (1995).
16) For the aldol reaction of pyrone, see: Paterson I., Wallace D. J., Tetra-
hedron Lett., 35, 9477—9480 (1994).
17) For the aldol reaction of pyrone, see: Munchhof M. J., Heathcock C.
H., J. Org. Chem., 59, 7566—7567 (1994).
18) For the aldol reaction of pyrone, see: Suh H., Wilcox C. S., J. Am.
Chem. Soc., 110, 470—481 (1988).
19) For the aldol reaction of pyrone, see: Ichihara A., Miki M., Tazaki H.,
Sakamura S., Tetrahedron Lett., 28, 1175—1178 (1987).
20) For the aldol reaction of pyrone, see: Williams D. R., White F. H., J.
Org. Chem., 52, 5067—5079 (1987).
21) For the aldol reaction of pyrone, see: Wachter M. P., Harris T. M.,
Tetrahedron, 26, 1685—1694 (1970).
22) For the alkylation of pyrone, see: Doundoulakis T., Xiang A. X., Lira
R., Agrios K. A., Webber S. E., Sisson W., Aust R. M., Shah A. M.,
Showalter R. E., Appleman J. R., Simonsen K. B., Bioorg. Med. Chem.
Lett., 14, 5667—5672 (2004).
23) For the alkylation of pyrone, see: Jones R. C. F., Patience J. M., Tetra-
hedron Lett., 30, 3217—3218 (1989).
24) For the alkylation of pyrone, see: Groutas W. C., Huang T. L., Stanga
M. A., Brubaker M. J., Moi M. K., J. Heterocyclic Chem., 22, 433—
435 (1985).
(1E,3E,5E,7E)-9-(Dimethoxyphosphinyl)-1-{4-benzyloxy-3-(2,3,4,6-
tetra-O-benzyl-a-D-galactopyranosyl)-2-pyrone}-1,3,5,7-nonatetraene
(4) To a stirred solution of vinyl stannane 5 (0.064 g, 0.145 mmol) and
vinyl bromide 15 (0.064 g, 0.073 mmol) in DMF (1.0 ml) was added
Pd2(dba)3 (0.001 g, 0.001 mmol) and AsPh3 (0.022 g, 0.073 mmol) succes-
sively. The resultant mixture was stirred for 30 min at 70 °C. Water was
added to the reaction mixture and extracted with AcOEt. The organic extract
was washed with Brine, dried with Na2SO4, then filtered, and evaporated in
vacuo. After the residue was purified by short plug of silica gel, the resultant
oil was purified by chromatography (preparative TLC; silica gel, AcOEt) in
the dark room with a red light to afford coupling product 4 (0.043 g, 63%) as
yellow oil.
Rf 0.2 (AcOEt). [a]D21 ꢀ6.37° (cꢁ0.472, MeOH). IR (neat) cmꢀ1: 2254,
1
2128, 1661, 1448, 1410, 1025. H-NMR (600 MHz, DMSO-d6, mixture of
rotamers): d 2.79 (1H, d, Jꢁ22.9 Hz), 2.80 (1H, d, Jꢁ22.9 Hz), 3.45—3.56
(2H, m), 3.61 (1.5H, s), 3.61 (1.5H, s), 3.63 (1.5H, s), 3.63 (1.5H, s), 3.66—
3.74 (2H, m), 4.05—4.06 (1H, m), 4.24 (0.5H, d, Jꢁ11.6 Hz), 4.38 (0.5H, d,
Jꢁ12.0 Hz), 4.39 (0.5H, d, Jꢁ12.0 Hz), 4.41 (0.5H, d, Jꢁ11.9 Hz), 4.45
(0.5H, d, Jꢁ11.9 Hz), 4.46—4.49 (1H, m), 4.47 (0.5H, d, Jꢁ12.3 Hz),
4.55—4.60 (2H, m), 4.64 (0.5H, d, Jꢁ11.9 Hz), 4.65 (0.5H, d, Jꢁ12.1 Hz),
4.73—4.79 (2H, m), 4.83 (0.5H, d, Jꢁ13.0 Hz), 4.85 (0.5H, d, Jꢁ13.0 Hz),
5.09 (0.5H, d, Jꢁ13.1 Hz), 5.22 (0.5H, d, Jꢁ13.1 Hz), 5.28 (0.5H, d, Jꢁ
12.7 Hz), 5.33 (0.5H, d, Jꢁ12.7 Hz), 5.69—5.76 (1H, m), 6.29 (0.5H, d, Jꢁ
15.2 Hz), 6.30 (0.5H, d, Jꢁ15.1 Hz), 6.32—6.39 (2H, m), 6.43—6.51 (2H,
m), 6.65 (0.5H, s), 6.66 (0.5H, s), 6.71 (1H, dd, Jꢁ11.1, 14.5 Hz), 6.99—
7.43 (26H, m). 13C-NMR (100 MHz, DMSO-d6, mixture of rotamers): d
28.9 (d, Jꢁ135 Hz), 52.5, 52.6, 69.3, 70.2, 70.6, 71.3, 72.1, 72.5, 72.6, 73.8,
74.0, 74.1, 74.5, 74.6, 75.0, 75.7, 76.9, 77.1, 84.4, 84.5, 97.2, 97.7, 102.5,
102.8, 122.4, 125.7, 125.8, 127.2, 127.3, 127.4, 127.5, 127.5, 127.5, 127.6,
127.7, 127.7, 127.9, 128.0, 128.1, 128.1, 128.2, 128.3, 128.4, 128.4, 128.4,
128.7, 131.6, 131.6, 132.0, 132.1, 134.7, 134.8, 135.8, 135.8, 135.9, 136.0,
138.3, 138.3, 138.9, 139.0, 139.0, 139.1, 139.2, 139.2, 139.3, 139.4, 158.9,
159.7, 160.8, 163.6, 167.9, 168.4. HR-ESI-MS m/z: Calcd for C57H59O11NaP
([MꢂNa]ꢂ) 973.3687, Found 973.668.
25) Since all protective groups are desirable to be deprotected in one oper-
ation at the final step, benzyl group was chosen as the protective
group.
26) Direct C-glycosylation of 4-benzyloxy-6-methyl pyrone gave only a-
C-glycoside in low yield.
27) Protection of the hydroxyl group of pyrone moiety proceeded
smoothly to afford the corresponding benzyl ether 7 in 86% yield as a
mixture of rotamers under Mitsunobu conditions (DEAD, PPh3 and
1
BnOH).The H-NMR (CDCl3 at 25 °C) of benzyl protected pyrone 7
was rather complex, and it seemed to be a mixture of two isomers.
However, the 1H-NMR of 7 in DMSO-d6 at 80 °C was gathered and
bundled to single isomer. That means that C3-b-galactopyranosyl-4-
benzyloxy-6-methylpyrone might exist as a mixture of rotamer at
25 °C. In contrast, a rotamer was not observed in the case of the corre-
sponding a-isomer.
Acknowledgements We would like to thank Central Glass Co., Ltd. for

March 2007
499
28) Strand D., Rein T., Org. Lett., 7, 199—202 (2005).
(2001).
29) The reaction was monitored by TLC analyses before it was quenched, 33) Aldehyde 6 was prepared from pyridinium-1-sulfonate according to
alcohol 12 was major product, however after being quenched, triene 11 the literature, see: Becher J., Org. Synth., 59, 79—84 (1979).
was major product. Alcohol 12 has corelation of terminal methyl pro- 34) Mukaiyama aldol-type reaction using aldehyde 6 was reported, see:
ton and methine proton of carbon bearing hydroxyl group in the
COSY spectrum.
Paterson I., Florence G. J., Heimann A. C., Mackay A. C., Angew.
Chem. Int. Ed., 44, 1130—1133 (2005).
30) Overman L. E., J. Am. Chem. Soc., 96, 597—599 (1974).
31) Nishikawa T., Asai M., Ohyabu N., Isobe M., J. Org. Chem., 63, 188—
192 (1988), and references therein.
35) Attempted direct dehydration of 14 with CCl3COCl and Et3N gave the
desired triene 15 only in 30% yield due to competitive retro aldol reac-
tion.
32) Saito S., Nagahara T., Yamamoto H., Synlett, 2001, 1690—1692