Stereoselective synthesis of the C31-C40/C43-C52 unit of amphidinol 3

Article abstract of DOI:10.1021/jo901793f

(Chemical Equation Presented) A concise synthesis of a tetrahydropyran ring system corresponding to the C31-C40 and C43-C52 units of amphidinol 3 is described. Successive chemoselective reactions, i.e., cross-metathesis to differentiate the iodoolefin fro

Full text of DOI:10.1021/jo901793f

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pores in a sterol dependent manner.3 The Amphidinium sp. are
Stereoselective Synthesis of the C31-C40/C43-C52
Unit of Amphidinol 3
known to produce a number of congeners,4 in which AM3 is the
most potent antifungal. The molecular structure of AM3 was
determined in 1999 based on the JBCA method,5 modified
Mosher method,6 and degradation of the natural product via
oxidative cleavage,2b and the absolute configuration at C2 has
recently been revised to be R, based on the chemical synthesis of
partial structures corresponding to the C1-C14 moiety, and
GC-MS analysis using a chiral capillary column of a degrada-
tion product derived from olefin cross-metathesis.7 Distinct
structural features represented by the amphidinols are a long
hydrophilic polyol chain, substituted tetrahydropyran (THP)
ring systems, and a hydrophobic polyene unit. The middle
portion containing the two THP rings is highly conserved
among the congeners, and structural diversity arises from the
polyol and polyene moieties. These structural features of AM3
have attracted considerable attention from the synthetic com-
munity, and a number of synthetic studies of AM3 have been
reported.8-12 Herein we report a concise synthesis of a THP ring
system corresponding to the C31-C40/C43-C52 unit of AM3.
Mitsunori Kanemoto, Michio Murata, and Tohru Oishi*
Department of Chemistry, Graduate School of Science, Osaka
University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043,
Japan
oishi@chem.sci.osaka-u.ac.jp
Received August 20, 2009
A concise synthesis of a tetrahydropyran ring system
corresponding to the C31-C40 and C43-C52 units of
amphidinol 3 is described. Successive chemoselective
reactions, i.e., cross-metathesis to differentiate the iodoo-
lefin from the terminal olefin and Sharpless asymmetric
dihydroxylation on the resulting E-olefin, resulted in
expeditious synthesis of an intermediate that was then
cross-coupled to afford an E,E-diene system. Four conti-
guous stereogenic centers were installed via construction
of the tetrahydropyran ring by means of Katsuki-Sharp-
less asymmetric epoxidation, 6-endo-tet cyclization, and
Sharpless asymmetric dihydroxylation.
FIGURE 1. Structure of amphidinol 3 (AM3, 1).
Marine dinoflagellates are a rich source of biologically and
structurally unique secondary metabolites.1 Amphidinol 3
(AM3, 1), produced by the dinoflagellate Amphidinium klebsii,
elicits potent antifungal activity (Figure 1).2 The biological
activity can be accounted for by formation of ion-permeable
(5) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866–876.
(6) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096. (b) Rieser, M. J.; Hui, Y.-H.; Rupprecht, J. K.;
Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.; Hanson, P. R.; Zhuang,
Z.; Hoye, T. R. J. Am. Chem. Soc. 1992, 114, 10203–10213. (c) Dale, J. A.;
Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519. (d) Sullivan, G. R.; Dale,
J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143–2147.
(1) (a) Shimizu, Y. Chem. Rev. 1993, 93, 1685. (b) Yasumoto, T.; Murata,
M. Chem. Rev. 1993, 93, 1897.
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2005, 61, 8606–8610. (c) Echigoyaa, R.; Rhodesb, L.; Oshimaa, Y.; Satakea,
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Jourdain, P.; Marko, I. E. Synlett 2007, 2286–2288. (c) Colobert, F.; Kreuzer,
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8810 J. Org. Chem. 2009, 74, 8810–8813
Published on Web 10/23/2009
DOI: 10.1021/jo901793f
r
2009 American Chemical Society

Kanemoto et al.
JOCNote
Although syntheses of the THP ring moieties of AM3 have
been reported by Roush,9b Rychnovsky,10a Paquette,11b and
Marko, we envisaged a novel strategy for synthesizing 2 as
TABLE 1. Chemoselective Cross-Metathesis of 4 and 5
ꢀ 12
shown in Scheme 1. The stereogenic centers of 2 would be
installed by means of Sharpless asymmetric dihydroxylation
(SAD)13 with respect to C32-C33 (C51-C50) and C38-C39
(C45-C44), and Katsuki-Sharpless asymmetric epoxidation
(SAE)14 at C34-C35 (C49-C48) via 6-endo-tet cyclization.15
The remaining stereogenic center corresponding to C36 (C47)
was to be derived from iodoolefin 4via its attachment to building
blocks 5 and 3 by means of cross-metathesis and cross-coupling
reactions, respectively.
entry
5 /equiv
solvent
temp/°Ca
yield/%
E/Z ratiob
1c
2c
3c
4c
5d
2
4
4
4
4
CH2Cl2
CH2Cl2
(CH2Cl)2
toluene
CH2Cl2
40
40
83
110
40
65
88
78
76
71
5.0/1
5.0/1
4.3/1
3.5/1
4.0/1
SCHEME 1. Synthesis Plan of the C31-C40/C43-C52 Unit
(2) of AM3
aThe reactions were carried out under reflux. bDetermined by NMR.
c10 mol % of 6 was used. d2 mol % of 6 was used.
SCHEME 2. Synthesis of the C31-C40/C43-C52 Segment (2)
Previously, we reported the synthesis of iodoolefin 4 via
lipase-catalyzed kinetic resolution.7 The iodoolefin 4 was
utilized for stereoselective synthesis of the C1-C14 unit of
AM3 through chemoselective cross-metathesis8a,16 as a key
step. The method was also applied for coupling with Z-olefin
5 as shown in Table 1. The cross-metathesis reaction of the
terminal olefin of 4 with 2 or 4 equiv of Z-olefin 517 using
10 mol % Grubbs second-generation catalyst 618 in CH2Cl2
at 40 °C (reflux) proceeded selectively in the presence of the
iodoolefin to afford diene 7 in 65% and 88% yields as a
mixture of E- and Z-isomers in a 5.0:1 ratio (entries 1 and 2).
Attempts to improve the E/Z ratio by using solvents of
higher boiling points were unsuccessful, e.g., E/Z = 4.3:1
in 1,2-dichloroethane at 83 °C (entry 3) and 3.5:1 in toluene
at 110 °C (entry 4). The catalyst loading could be reduced to
2 mol % (entry 5); however, the yield of 7 (71%) and the E/Z
ratio (4.0: 1) were somewhat lower than those in entry 2.
Next, we moved on to the second chemoselective reaction,
SAD of 7 using AD-mix-β (Scheme 2). As expected, the less
hindered and electron-rich olefin, in the presence of the iodo-
olefin, reacted stereoselectively to afford diol 8 in 68% yield,
(13) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547. (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.;
Wang, Z. M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768–2771.
(14) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976. (b) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(15) (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K.
Chem. Commun. 1985, 1359–1362. (b) Nicolaou, K. C.; Nugiel, D. A.;
Couladouros, E.; Hwang, C.-K. Tetrahedron 1990, 46, 4517–4552.
(16) For recent application to natural product synthesis, see: (a)
BouzBouz, S.; Roche, C.; Cossy, J. Synlett 2009, 803–807. (b) Ferrie, L.;
Boulard, L.; Pradaux, F.; Bouzbouz, S.; Reymond, S.; Capdevielle, P.;
Cossy, J. J. Org. Chem. 2008, 73, 1864–1880. (c) Amans, D.; Bellosta, V.;
Cossy, J. Org. Lett. 2007, 9, 1453–1456.
which was separated from the other stereoisomers including the
diols derived from the Z-olefin (18%). Protection of the hydroxy
groups as acetates, followed by Migita-Kosugi-Stille coupl-
ing reaction19 with stannane 320 resulted in the formation of the
(17) Charette, A. B.; Gagnon, A.; Fournier, J.-F. J. Am. Chem. Soc. 2002,
124, 386–387.
(19) (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771–1780. (b) Stille, J. K.
Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(20) (a) Smith, A. B.; Zheng, J. Tetrahedron 2002, 58, 6455–6471. (b)
Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851–3854.
J. Org. Chem. Vol. 74, No. 22, 2009 8811

Kanemoto et al.
JOCNote
E,E-diene in 92% yield. Removal of the TBS group with HF Py
(2R,3R,5R,E)-1-Benzyloxy-5-(tert-butyldimethylsilyloxy)-7-
iodohept-6-ene-2,3-diol (8). A mixture of K2OsO4 2H2O (31.3
3
at 0 to 35 °C in THF provided allylic alcohol 11, which was
subjected to SAE, using D-(-)-DET to furnish vinyl epoxide 12.
Solvolysis of the acetate with K2CO3 in MeOH, and successive
treatment of the resulting epoxy alcohol 13 with PPTS resulted in
6-endo-tet cyclization to afford the THP ring 14 in 60% yield for
three steps. The structure of 14 was confirmed by NOE experi-
ments of the corresponding triacetate 17 (Figure 2), i.e., NOEs
between H38 and H33, and H38 and H36 were observed,
in which H36 and H38 occupied 1,3-diaxial positions
(JH36-H37ax = 12.0 Hz, JH37ax-H38 = 12.0 Hz). Protection of
the triol 14 as TBS ethers with TBSOTf/2,6-lutidine furnished 15
in 79% yield. SAD of 15 with AD-mix-β proceeded stereoselec-
tively to afford the desired diol 16 in 97% yield (dr = 10: 1), and
protection of the resulting vicinal diol as TBS ethers provided 2.
The overall yield of 2 from the iodoolefin 4 was 20% over 11
steps. The fully protected 2 would be a key intermediate
corresponding to both the C31-C40 and C43-C52 units of
AM3, in which protecting groups of the primary alcohols can be
selectively removed under oxidative (for PMB ether) or reductive
(for benzyl ether) conditions in the presence of TBS ethers.
3
mg, 0.0851 mmol), (DHQD)2PHAL (331 mg, 0.425 mmol),
K3Fe(CN)6 (8.40 g, 25.5 mmol), K2CO3 (3.52 g, 25.5 mmol),
and MeSO2NH2 (2.42 g, 25.5 mmol) in t-BuOH (18 mL) and
H2O (28 mL) was stirred at room temperature for 30 min, and
then cooled to 0 °C. To the resulting suspension was added a
solution of 7 (3.87 g, 8.51 mmol) in t-BuOH (10 mL). After being
stirred for 36 h at 0 °C, the resulting mixture was quenched with
solid Na2S2O3 5H2O (8.0 g) and allowed to warm to room
3
temperature over 1 h. The aqueous layer was extracted with
EtOAc, and the combined organic layers were washed with
saturated aqueous NaCl, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. Purification by flash
silica gel column chromatography (hexane/EtOAc = 5/1 f
3/1 f 2/1) afforded 8 (2.27 g, 68%) as a yellow syrup:
[R]27 þ37.8 (c 0.89, CHCl3); Rf 0.40 (hexane/EtOAc = 2/1);
D
IR (film) ν 3433, 2953, 2928, 2888, 2856, 1253, 1077 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.35-7.26 (m, 5H), 6.54 (dd, J =
14.4, 5.8 Hz, 1H), 6.27 (dd, J = 14.4, 1.2 Hz, 1H), 4.55 (d, J =
11.8 Hz, 1H), 4.51 (d, J = 11.8 Hz, 1H), 4.42 (m, 1H), 3.89 (d,
J = 10.5 Hz, 1H), 3.59-3.51 (m, 3H), 3.09 (br s, 1H), 2.62 (br s,
1H), 1.79 (ddd, J = 14.2, 10.5, 3.4 Hz, 1H), 1.53 (ddd, J = 14.2,
7.2, 2.2 Hz, 1H), 0.88 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 148.2, 137.7, 128.5, 127.9, 127.8, 76.3, 73.6,
72.9, 72.1, 68.5, 40.2, 25.8, 18.1, -4.6, -5.2; HRMS (ESI-TOF)
calcd for C20H33IO4SiNa [(M þ Na)þ] 515.1091, found
515.1102.
(2R,3R,5R,6E,8E)-1-Benzyloxy-5-(tert-butyldimethylsilyloxy)-
10-(4-methoxybenzyloxy)deca-6,8-diene-2,3-diyl Diacetate (10).
To a solution of 9 (3.28 g, 5.68 mmol) and 3 (2.92 g, 6.25 mmol)
in DMF (18.9 mL) was added PdCl2(MeCN)2 (36.8 mg, 0.142
mmol, 2.5 mol %) at 0 °C then the mixture was stirred at room
temperature for 7 h. The resulting mixture was quenched with
aqueous NaHCO3 and diluted with Et2O. The organic layer was
separated, and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with saturated aqueous
NaCl, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. Purification by silica gel column chro-
matography (hexane/EtOAc = 10/1 f 8/1 f 4/1) afforded 10
(3.29 g, 92%) as a colorless syrup: [R]26D þ8.92 (c 0.75, CHCl3);
Rf 0.48 (hexane/EtOAc = 2/1); IR (film) ν 2954, 2929, 2857,
1744, 1513, 1372, 1250, 1224, 1097, 1039 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.33-7.23 (m, 7H), 6.86 (m, 2H), 6.19 (dd, J =
15.0, 10.6 Hz, 1H), 6.11 (dd, J = 15.0, 10.6 Hz, 1H), 5.75 (dt,
J = 15.0, 6.0 Hz, 1H), 5.58 (dd, J = 15.0, 7.4 Hz, 1H), 5.29 (ddd,
J = 8.4, 4.0, 4.0 Hz, 1H), 5.16 (m, 1H), 4.51 (d, J = 12.0 Hz, 1H),
4.44 (d, J = 12.0 Hz, 1H), 4.43 (s, 2H), 4.13 (m, 1H), 4.00 (d, J =
6.0 Hz, 2H), 3.78 (s, 3H), 3.53 (dd, J = 10.5, 4.6 Hz, 1H), 3.50
(dd, J = 10.5, 6.0 Hz, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.74 (ddd,
J = 14.2, 7.9, 4.0 Hz, 1H), 1.69 (ddd, J = 14.2, 8.4, 4.6 Hz, 1H),
0.86 (s, 9H), 0.01 (s, 3H), -0.03 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.2, 170.0, 159.1, 137.7, 136.4, 131.7, 130.2, 129.9,
129.4, 129.3, 128.2, 127.6, 113.7, 73.0, 72.7, 71.8, 70.1, 69.9, 69.1,
68.5, 55.2, 39.5, 25.8, 20.9. 20.8, 18.0, -4.0, -5.1; HRMS
(ESI-TOF) calcd for C35H50O8SiNa [(M þ Na)þ] 649.3173,
found 649.3193.
FIGURE 2. Structure determination of 17 by NMR analysis.
In conclusion, a concise synthesis of the tetrahydropyran
ring system 2, corresponding to the C31-40/C43-C52 unit
of AM3, was achieved based on chemoselective cross-
metathesis, regioselective dihydroxylation, and 6-endo-tet
cyclization. On the basis of the present method, it would be
possible to synthesize an enantiomer of 2 from an enantio-
mer of 4 by changing the ligands used in SAD and SAE.
Experimental Section
(3R,1E,5E)-7-Benzyloxy-3-(tert-butyldimethylsilyloxy)-1-io-
dohepta-1,5-diene (7). To a solution of 4 (5.01 g, 14.8 mmol) and
5 (15.9 g, 59.2 mmol) in CH2Cl2 (48 mL) under reflux was added
a solution of Grubbs catalyst 6 (251 mg, 0.296 mmol, 2 mol %)
in CH2Cl2 (1.0 mL). After being stirred for 6 h, the reaction
mixture was cooled to 0 °C, quenched with Et3N, and allowed
to warm to room temperature over 1 h, then the solvent
was removed under reduced pressure. Purification by silica gel
column chromatography (hexane/EtOAc = 1/0 f 20/1 f 10/1)
afforded a mixture of 7 and allyl benzyl ether. The allyl benzyl
ether was removed under reduced pressure at 90 °C for 1 h to
provide 7 (4.81 g, 71%) as a yellow oil: [R]26 þ6.84 (c 1.05,
(2S,3R,4R,6R)-6-[(1R)-2-Benzyloxy-1-hydroxyethyl]-2-[(E)-
3-(4-methoxybenzyloxy)prop-1-enyl]tetrahydropyran-3,4-diol
(14). To a mixture of powdered MS4A (450 mg) in CH2Cl2
(8 mL) were added D-(-)-DET (127 μL, 0.732 mmol) and Ti(Oi-
Pr)4 (174 μL, 0.585 mmol) at -25 °C. After the mixture was
stirred for 30 min, a solution of 11 (1.50 g, 2.96 mmol) in CH2Cl2
(6 mL) was added. After an additional 30 min of stirring, a
solution of 2.8 M TBHP in CH2Cl2 (2.1 mL, 5.85 mmol) was
added. Then after being stirred for 18 h at -20 °C, the resulting
mixture was quenched with saturated aqueous Na2S2O3, diluted
with EtOAc, and allowed to warm to room temperature. The
D
CHCl3); Rf = 0.40 (hexane/EtOAc = 10/1); IR (film) ν 2953,
2928, 2884, 2856, 1606, 1471, 1361, 1254, 1088, cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.33-7.25 (m, 5H), 6.51 (dd, J = 14.3, 6.0
Hz, 1H), 6.21 (dd, J = 14.3, 1.3 Hz, 1H), 5.74-5.54 (m, 2H),
4.41 (s, 2H), 4.11 (tdd, J = 6.0, 6.0, 1.3 Hz, 1H), 3.96 (d, J = 6.0
Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 148.5 138.4, 129.7,
129.2, 128.4, 127.7, 127.5, 76.0, 74.8, 71.9, 70.6, 65.8, 40.6, 35.9,
25.8, 18.1, -4.6, -4.9; HRMS (ESI-TOF) calcd for C20H31IO2-
SiNa [(M þ Na)þ] 481.1036, found 481.1033.
8812 J. Org. Chem. Vol. 74, No. 22, 2009

Kanemoto et al.
JOCNote
precipitates were removed by filtration through a Celite pad. The
organic layer was separated, and the aqueous solution was
extracted with EtOAc. The combined organic layers were washed
with saturated aqueous NaCl, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. Purification
by silica gel column chromatography (hexane/EtOAc = 1/1)
afforded a mixture of 12 and D-(-)-DET as a yellow oil.
To a solution of the above mixture of 12 and D-(-)-DET in
MeOH (30 mL) was added K2CO3 (80 mg, 0.585 mmol) at 0 °C.
After being stirred for 3 h at 0 °C, the resulting mixture was
quenched with pH 7.0 phosphate buffer, then MeOH was
removed under reduced pressure. The aqueous layer was ex-
tracted with CH2Cl2, and the combined organic layers were
washed with saturated aqueous NaCl, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to
provide 13. This crude 13 was used for the next step without
further purification.
IR (film) ν 3387, 2910, 2864, 1612, 1513, 1454, 1248, 1096 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.31-7.19 (m, 7H), 6.86-6.82
(m, 2H), 5.79 (dt, J = 15.9, 5.4, 1.2 Hz, 1H), 5.65 (dd, J = 15.9,
4.4 Hz, 1H), 4.51 (br s, 1H), 4.49 (s, 2H), 4.39 (s, 2H), 3.92 (d,
J = 5.4 Hz, 2H), 3.81-3.74 (m, 2H), 3.76 (s, 3H), 3.71-3.68 (m,
2H), 3.54 (d, J = 6.0 Hz, 2H), 1.93 (ddd, J = 12.6, 12.6, 12.6 Hz,
1H), 1.61 (br d, J = 12.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 159.2, 137.9, 130.4, 130.0, 129.4, 128.4, 128.2, 127.7, 127.7, 76.9,
73.4, 72.4, 72.1, 71.0, 70.6, 69.7, 69.4, 65.9, 55.2, 30.9; HRMS
(ESI-TOF) calcd for C25H32O7Na [(M þ Na)þ] 467.2046,
found 467.2036.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (B) from Japan Societies for
the Promotion of Science. M.K. expresses special thanks to
The Global Center of Excellence (COE) Program “Global
Education and Research Center for Bio-Environmental
Chemistry” of Osaka University.
To a solution of the above crude 13 in CH2Cl2 (29mL) wasadded
PPTS (73.2 mg, 0.292 mmol) at 0 °C then the solution was stirred for
19 h. The resulting mixture was quenched with Et3N and concen-
trated under reduced pressure. Purification by silica gel column
chromatography (EtOAc/MeOH = 1/0 f 30/1 f 20/1 f
10/1) afforded 14 (782 mg, 60% for 3 steps) as a colorless syrup:
Supporting Information Available: General experimental
methods, additional experimental procedures, and copies of
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
[R]26 -23.7 (c 0.75, CHCl3); Rf 0.30 (hexane/EtOAc = 3/1);
D
J. Org. Chem. Vol. 74, No. 22, 2009 8813