Synthesis of the C8-C20 and C21-C30 segments of pectenotoxin 2

Article abstract of DOI:10.1016/j.tetlet.2007.04.136

In this study, we synthesized the C8-C20 and C21-C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8-C20 segment was assembled from a phosphonate corresponding to the C8-C15 segment (prepared from l-malic acid in 19 steps) and an aldehyd

Full text of DOI:10.1016/j.tetlet.2007.04.136

Tetrahedron Letters 48 (2007) 4523–4527
Synthesis of the C8–C20 and C21–C30 segments of pectenotoxin 2
Kenshu Fujiwara,* Yu-ichi Aki, Fuyuki Yamamoto, Mariko Kawamura,
Masanori Kobayashi, Azusa Okano, Daisuke Awakura, Shunsuke Shiga, Akio Murai,
Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 23 March 2007; revised 26 April 2007; accepted 27 April 2007
Available online 1 May 2007
Abstract—In this study, we synthesized the C8–C20 and C21–C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8–
C20 segment was assembled from a phosphonate corresponding to the C8–C15 segment (prepared from L-malic acid in 19 steps) and
an aldehyde corresponding to the C16–C20 segment (synthesized from 3-methyl-3-butenol in nine steps) by a twelve-step process
including the Horner–Wadsworth–Emmons reaction, regio- and stereoselective reduction of the resulting enone, diastereoselective
epoxidation, and 5-exo epoxide cleavage forming the C-ring. The C21–C30 segment was constructed in 13 steps from (S)-glycidol via
a route involving E-ring formation by 5-exo epoxide cleavage and stereoselective methylation at C27 by the Evans method.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The pectenotoxin (PTX) family of diarrhetic shellfish
toxins, which were isolated from toxin infected scallop
Patinopecten yessoensis and the dinoflagellate Dinophy-
sis fortii by Yasumoto,1 has an unusual thirty-four-
membered macrolactone that includes a spirocyclic
acetal AB-ring, a six-membered cyclic hemiacetal G-
ring, a bicyclic acetal D-ring, and three oxolanes (C,
E, and F-rings). While some PTXs show potent hepato-
toxicity in mice,2 recent studies have reported that PTX2
(1) (Fig. 1) also exhibits strong cytotoxicity against can-
cer cells3 and actin-depolymerizing activity.4 These
remarkable structural and biological features of PTXs
have attracted the attention of synthetic organic chem-
ists.5–7 As part of our goal toward total synthesis of
PTXs, we describe herein the synthesis of the C8–C20
and C21–C30 segments (2 and 3, respectively; Scheme
1) of PTX2 (1).
From the retrosynthetic perspective (Scheme 1), guided
by our previous synthesis of the C8–C18 segment of
PTX2,7b the C8–C20 synthetic segment (2) was envi-
sioned to arise via a 5-exo epoxide cleavage reaction of
4, which would be assembled from phosphonate 5 and
aldehyde 6 through a route involving the Horner–Wads-
worth–Emmons reaction, regio- and stereoselective
reduction of the ketone at C14, and diastereoselective
epoxidation. Although we previously synthesized the
C8–C15 segment, which is structurally the same as 5
except for the protective group of the oxygen at C11,
it required a lengthy 26 step process from 3-butynol.7b
Therefore, we intended to prepare 5 by an alternative
shorter route including formation of enone 9 from 10,
diastereoselective reduction of 9 affording 8, diastereo-
selective epoxidation of 8 followed by protection giving
7, and construction of the b-keto-phosphonate part of 5.
Aldehyde 6, having a quaternary asymmetric center at
C18, would be derived from epoxy alcohol 11 exploiting
regioselective reductive cleavage followed by oxidation.
We also undertook the synthesis of the C21–C30 seg-
ment (3) from 12 through the Evans alkylation8 to make
C8-C20 Segment
O
8
Me
1
O
O
Me
B
O
C
O
A 7
O
33
OH
Me
O
HO
O
D
30
21
F
O
O
Me
Me
E
31
G
20
OH
Me Me
C21-C30 Segment
O
40
Pectenotoxin 2 (PTX2: 1)
Figure 1.
Keywords: Pectenotoxin 2; Natural product synthesis; Polyether
macrolide.
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.136

4524
K. Fujiwara et al. / Tetrahedron Letters 48 (2007) 4523–4527
OTBDPS
OTBDPS
HO
OTBDPS
OTBDPS
OTBS
14 OTBS
O
ref. 10
a
b
c
8
8
O
Me
15
OTMS
Me
10
16
15
C
O
OTMS
Me
O
TBSO
TBSO
HO
DMBO
OH
16
O
O
DMP 15
Me
PMBO
PMBO TMSO
OH
OH
16
20
L-Malic acid
20
SO2Ph
C8-C20 Segment (2)
DMP: 3,4-dimethoxyphenyl
ODMB
Me
4
OTBDPS
OTBDPS
e
HO
16
d
f
g
OTBDPS O
O
OTMS
Me
OHC
O
9
8
11
P(OMe)2
16
8
14
DMBO
CHO
17
DMBO
Me
18
18
15
+
OH
8 + epi-8
TBSO
PMBO
OTMS
Me
20
20
ODMB
ODMB
OTBDPS
OTBDPS S
5
6
11
k
m
S
O
12
R1O
Me
TBSO
l
OR
Me
OTBDPS
OTBDPS
OTBDPS
OTBDPS
8
8
8
8
R2O
PMBO
13
O
18: R1 = DMB, R2 = H
19: R1 = DMB, R2 = PMB
20: R1 = H, R2 = PMB
7: R1 = TBS, R2 = PMB
21: R = H
22: R = TMS
11
11
11
h
i
j
TBSO
Me DMBO
Me DMBO
Me HO
10
O
9
OH
PMBO
HO
8
7
OTBDPS
OTBDPS OH O
P(OMe)2
CHO
n
TBDPSO
TBDPSO
HO
TBDPSO
HO
o
OPMB
OH HO
Me
Me
5
O
F
O
F
Me
Me
30
21
O
TBSO
PMBO
23
OTMS
TBSO
OTMS
Me
Me
Me Me
C21-C30 Segment (3)
PMBO
12
13
14
24
Scheme 1.
Scheme 2. Reagents and conditions: (a) 3,4-dimethoxybenzaldehyde,
CSA (cat), toluene, reflux, 5 h, 15: 47%, recovered 10: 41%; (b)
DIBALH, CH2Cl2, ꢁ78 to 0 ꢁC, 30 min, 71%; (c) (COCl)2, DMSO,
CH2Cl2, ꢁ78 ꢁC, 10 min, then Et3N, ꢁ78 to 0 ꢁC, 15 min; (d) 2-
propenylmagnesium bromide, THF, ꢁ78 ꢁC, 10 min, 68% from 16; (e)
(COCl)2, DMSO, CH2Cl2, ꢁ78 ꢁC, 10 min, then Et3N, ꢁ78 to 0 ꢁC,
15 min, 90%; (f) Zn(BH4)2, Et2O, ꢁ30 ꢁC, 20 min, 71%; (g) VO(acac)2,
TBHP, CH2Cl2, 0 ꢁC, 3.5 h, 67%; (h) NaH, PMBBr, Bu4NI, THF,
23 ꢁC, 2 h, 83%; (i) DDQ, CH2Cl2—pH 7 buffer (10:1), 26 ꢁC, 3.5 h; (j)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 1 h, 71% from 19; (k) 1,3-
dithiane, t-BuLi, Bu2Mg, THF, ꢁ20 ꢁC, 30 min, then 7, 23 ꢁC, 1 h,
72%; (l) TMSOTf, 2,6-lutidine, DMF, 0 ꢁC, 70 min, 87%; (m)
Hg(ClO4)2, 2,6-di-tert-butylpyridine, THF–H2O (5:1), 25 ꢁC, 15 min,
72%; (n) (MeO)2P(O)CH3, BuLi, THF, ꢁ78 ꢁC, 30 min, then 23,
ꢁ78 ꢁC, 2 h, 97%; (o) DMPI, NaHCO3, CH2Cl2, 23 ꢁC, 5 min, 100%.
the stereocenter at C27 and the Wittig reaction to form
the trisubstituted double bond at C28 (Scheme 1). In
turn, the E-ring of 12 would arise via diastereoselective
epoxidation of bishomoallyl alcohol 14 followed by
the 5-exo epoxide cleavage reaction of the resulting
epoxide 13.9
Scheme 2 illustrates synthesis of phosphonate 5, starting
from known diol 10 prepared in four steps from L-malic
acid.10 Diol 10 was converted to 3,4-dimethoxy benzyl
(DMB) ether 16 through acetalization (47%: 79% based
on recovery of 10) followed by reductive cleavage with
DIBALH (71%). Swern oxidation11 of 16 and the subse-
quent reaction with 2-propenylmangesium bromide gave
a 1:1 mixture of 8 and its diastereomer (epi-8) (68% from
12). To establish stereochemistry at C11, an oxidation/
reduction process was applied. Swern oxidation11 of
the mixture of 8 and epi-8 (90%) and reduction of the
resulting 9 with Zn(BH4)2 afforded 8 as a sole product
(71%).12,13 Alcohol 8 was epoxidized with TBHP in
the presence of VO(acac) to produce 18 as an almost sin-
gle diastereomer (67%),14,15 which was then converted to
7 through a three-step process [protection with PMBBr
(83%), removal of DMB, and protection with TBSOTf
(71% from 19)]. Following Nakata’s procedure, epoxide
7 was reacted with 1,3-dithiane to give 21 in good yield
(72%).16 After TMS-protection of 21, the dithiane group
was hydrolyzed with Hg(ClO4)2 in the presence of 2,6-
di-tert-butylpyridine to produce 23 (72%),17,18 which
was reacted with lithiated dimethyl methylphosphonate
to afford 24 (97%). Finally, alcohol 24 was oxidized with
Aldehyde 6 was synthesized from 3-methyl-3-butenol
(25) (Scheme 3). Protection of 25 as a DMB ether
(64%) followed by a one-pot dihydroxylation/diol-cleav-
age process afforded 27 (68%), which was converted to
28 stereoselectively via the Horner–Wadsworth–
Emmons reaction (99%: E/Z = ꢀ2.7:1) and DIBALH
reduction (73% after separation). Katsuki–Sharpless
asymmetric epoxidation20 of 28 with (+)-diisopropyl
tartrate gave 11 (97%) in good optical yield (95% ee).21
Epoxide 11 was regioselectively cleaved with LiAlH4
to produce 29 (100%),22 which was transformed to 31
by a stepwise protection/deprotection process (95%
and 89%, respectively). Alcohol 31 was oxidized with
TPAP and NMO to aldehyde 6.23
Scheme 4 shows the synthesis of C8–C20 segment 2. The
coupling reaction of 5 with 6 and the subsequent C-ring
formation was performed following our previous proce-
dure.7b Phosphonate 5 was coupled with 6 by the Hor-
ner–Wadsworth–Emmons reaction to afford 32 (85%),
which was stereoselectively reduced to 33 under Luche
Dess–Martin periodinane (DMPI) to produce
5
(100%).19 Phosphonate 5 was thus synthesized from L-
malic acid in 19 steps.

K. Fujiwara et al. / Tetrahedron Letters 48 (2007) 4523–4527
4525
conditions (98%).24,25 Selective detachment of the TMS
group at C12-oxygene (93%) followed by hydroxy-direc-
ted epoxidation with m-CPBA gave a 3:1 mixture of
epoxide 35 and its diastereomer (95%).26 After selective
protection with TBSOTf, epoxide 4 was isolated with a
66% yield. Intramolecular 5-exo cyclization of 4 with a
catalytic amount of CSA led to 36 (77%).27 Thus, the
C-ring was successfully constructed. Diol 36 was then
transformed with triphosgene to carbonate 37 (95%),
of which the DMB group was removed with TMSOTf/
2,6-lutidine to give 38 (95%).28 Installation of a phenyl-
thio group to 38 with N-(phenylthio)phthalimide/Bu3P
to afford 39 (94%)29 followed by a two-step process
including removal of the carbonate of 39 with LiAlH4
(100%) and protection of diol 40 with TMSOTf pro-
duced 41 in good yield (93%). Finally, sulfide 41 was oxi-
dized with m-CPBA (100%), thereby completing the
synthesis of the C8–C20 segment (2)30 of PTX2 (1).
Me
Me
Me OH
28
b
c, d
RO
DMBO
O
DMBO
25: R = H
26: R = DMB
27
a
R1O
OR2
18
e
f
i
DMBO
11
6
Me
29: R1 = R2 = H
g
h
30: R1 = R2 = TMS
31: R1 = H, R2 = TMS
Scheme 3. Reagents and conditions: (a) NaH, 3,4-dimethoxybenzyl
chloride, Bu4NI, THF, 25 ꢁC, 24 h, 64%; (b) OsO4, NMO, 1,4-
dioxane—pH 7 buffer (3:1), 23 ꢁC, 1 h, then NaIO4, 3 h, 68%; (c)
(EtO)2(O)PCH2CO2Et, NaH, THF, 23 ꢁC, 12.5 h, 99% (E/Z =
ꢀ2.7:1); (d) DIBALH, CH2Cl2, ꢁ78 ꢁC, 40 min, then separation,
73%; (e) (+)-diisopropyl tartrate, Ti(Oi-Pr)4, TBHP, MS4A, CH2Cl2,
ꢁ30 ꢁC, 12 h, 97% (95% ee); (f) LiAlH4, THF, 24 ꢁC, 1 h, 100%; (g)
TMSOTf, 2,6-lutidine, CH2Cl2, ꢁ40 ꢁC, 45 min, 95%; (h) K2CO3,
MeOH, 23 ꢁC, 90 s, 89%; (i) TPAP, NMO, MS4A, CH2Cl2, 0 ꢁC,
30 min, 87%.
C21–C30 segment 3 was constructed from (S)-glycidol
(42) (Scheme 5). Protection of 42 with TBDPSCl
(100%) and the subsequent reaction with 2-methyl-3-
propenylmagnesium chloride afforded 14 (100%). When
bishomoallyl alcohol 14 was subjected to epoxidation
with TBHP/VO(acac)2 followed by treatment with
CSA, the desired oxolane 12 was produced predomi-
nantly (57%) along with its diastereomer (epi-12: 18%)
and recovered 14 (11%).9,31 Swern oxidation of 12 affor-
ded 44 (96%),11 which was converted to 46 by the
OTBDPS
O
a
5
OTMS
Me
TBSO
PMBO
OTMS
Me
6
DMBO
b
32
OTBDPS
OTBDPS
OR
O
OH
14
RO
TBDPSO
TBDPSO
Me
Me
OTMS
Me
OTMS
Me
d
b
c
d
21
O
O
OHC
TBSO
TBSO
OH
Me
OR
Me
HO
O
14
25
PMBO
PMBO
DMBO
35: R = H
4: R = TBS
DMBO
33: R = TMS
34: R = H
42: R = H
43: R = TBDPS
12
44
a
e
c
f
TBDPSO
TBDPSO
O
O
O
O
Me
e, f
Me
g
OTBDPS
Me
OTBDPS
O
O
OTBS
OTBS
OH
O
N
O
N
O
O
O
Me
Me
P(OEt)2
g
O
O
O
N
i-Pr
i-Pr
46
TBSO
TBSO
47
12
15
O
O
16
PMBO
O
PMBO
OH
Me
i-Pr
45
18
Me
R
DMBO
TBDPSO
Me
19
OR1
Me Me
R2O
Me
j
37: R = ODMB
38: R = OH
39: R = SPh
36
O
O
OHC
h
i
h, i
j, k
m
3
OTBDPS
Me
O
Me
48
OTBS
OR
PPh3
Me
50: R1 = H
EtO
R2 = TBDPS
51: R1 = PMB
R2 = TBDPS
49
l
TBSO
PMBO
O
l
2
OR
Me
PhS
Scheme 5. Reagents and conditions: (a) TBDPSCl, imidazole, DMF,
25 ꢁC, 1 h, 100%; (b) 3-chloro-2-methylpropene, Mg, THF, 24 ꢁC, 1 h,
then 43, ꢁ40 ꢁC, 5 h, 100%; (c) VO(acac)2 (cat.), TBHP, benzene,
55 ꢁC, 21 h, then CSA (cat.), 21 ꢁC, 2 h, 12: 57%, epi-12: 18%,
recovered 14: 11%; (d) (COCl)2, DMSO, CH2Cl2, ꢁ78 ꢁC, 35 min, then
Et3N, ꢁ78 to 0 ꢁC, 75 min, 96%; (e) 45, NaH, THF, 23 ꢁC, 30 min,
then 44, 23 ꢁC, 1.5 h, 93%; (f) H2, Pd/C, EtOH, 23 ꢁC, 16 h, 100%; (g)
NaHMDS, THF, ꢁ78 ꢁC, 1 h, then MeI, ꢁ78 ꢁC, 4 h, 93%; (h)
NaBH4, THF–H2O (3:1), 23 ꢁC, 22 h, 100%; (i) (COCl)2, DMSO,
CH2Cl2, ꢁ78 to ꢁ50 ꢁC, 15 min, then Et3N, ꢁ50 to 0 ꢁC, 30 min, 97%;
(j) 49 (excess), benzene, reflux, 56 h; (k) DIBALH, CH2Cl2, ꢁ78 ꢁC,
25 min, 92% from 48; (l) NaH, PMBBr, Bu4NI, THF, 23 ꢁC, 16 h,
96%; (m) Bu4NF, THF, 23 ꢁC, 1.5 h, 100%.
40: R = H
41: R = TMS
k
Scheme 4. Reagents and conditions. (a) NaH, benzene–THF (2:5),
0 ꢁC, 5 min, then 6, ꢁ78 ꢁC, 8 h, 85%; (b) NaBH4, CeCl3ÆH2O, EtOH,
ꢁ20 ꢁC, 3 h, 98%; (c) K2CO3, MeOH, 24 ꢁC, 2 h, 93%; (d) m-CPBA,
NaHCO3, CH2Cl2, 0 ꢁC, 2 h, 95% (dr = 3:1); (e) TBSOTf, 2,6-lutidine,
CH2Cl2, ꢁ20 ꢁC, 1 h, then separation, 66%; (f) CSA (cat.), CH2Cl2,
0 ꢁC, 4 h, 77%; (g) (CCl3O)2CO, pyridine, CH2Cl2, 0 ꢁC, 2 h, 95%; (h)
TMSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 2 h, 95%; (i) N-(phenyl-
thio)phthalimide, Bu3P, CH2Cl2, 25 ꢁC, 1 h, 94%; (j) LiAlH4, Et2O,
ꢁ30 ꢁC, 1.5 h, 100%; (k) TMSOTf, 2,6-lutidine, CH2Cl2, ꢁ30 ꢁC, 3 h,
93%; (l) m-CPBA, NaHCO3, CH2Cl2, 25 ꢁC, 1 h, 100%.

4526
K. Fujiwara et al. / Tetrahedron Letters 48 (2007) 4523–4527
Horner–Wadsworth–Emmons reaction with 45 (93%)32
and the subsequent hydrogenation (100%). Stereo-
selective methylation of 46 by the Evans method to
give 47 (93%), reductive detachment of the chiral auxi-
liary (100%), and then Swern oxidation provided 48
(97%).11 Aldehyde 48 was reacted with Wittig reagent
49, and the resulting unsaturated ester was reduced with
DIBALH to afford 50 stereoselectively (92% from 48).
The final protection/deprotection process transformed
50 to 333,34 (96% for two steps). Thus, the synthesis of
the C21–C30 segment (3) of PTX2 (1) was
accomplished.
Acknowledgments
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS and NMR Laboratory, Graduate School of
Agriculture, Hokkaido University) for the measure-
ments of mass spectra. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japanese Government.
References and notes
In conclusion, we successfully synthesized the C8–C20
and C21–C30 segments (2 and 3, respectively) of
PTX2 (1). C8–C20 segment 2 was assembled from phos-
phonate 5 (prepared from L-malic acid in nineteen steps)
and aldehyde 6 (synthesized from 3-methyl-3-butenol in
nine steps) by a twelve-step process including the
Horner–Wadsworth–Emmons reaction, regio- and ster-
eoselective reduction of the resulting enone, diastereose-
lective epoxidation, and 5-exo epoxide cleavage forming
the C-ring. C21–C30 segment 3 was constructed in thir-
teen steps from (S)-glycidol via a route involving E-ring
formation by 5-exo epoxide cleavage, stereoselective
methylation at C27, and formation of the trisubstituted
olefin at C28. All newly generated stereocenters of 2 and
3 were properly confirmed by the NMR or [a]D analysis
of the intermediates or derivatives from the intermedi-
ates (Figs. 2–4).13,15,22,25,27,31,33 Further efforts toward
the total synthesis of PTX2 are currently underway in
our laboratory.
1. (a) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.;
Matsumoto, G. K.; Clardy, J. Tetrahedron 1985, 41, 1019;
(b) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org.
Chem. 1998, 63, 2475; (c) Sasaki, K.; Satake, M.;
Yasumoto, T. Biosci. Biotech. Biochem. 1997, 61, 1783.
2. (a) Ishige, M.; Sato, N.; Yasumoto, T. Rep. Hokkaido Inst.
Public Health 1988, 38, 15; (b) Terao, K.; Ito, E.; Yanagi,
T.; Yasumoto, T. Toxicon 1986, 24, 1141.
3. Jung, J. H.; Sim, C. J.; Lee, C.-O. J. Nat. Prod. 1995, 58,
1722.
4. (a) Zhou, Z.-H.; Komiyama, M.; Terao, K.; Shimada, Y.
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5. The total synthesis of pectenotoxins-4 and -8, see: (a)
Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4569; (b) Evans, D. A.;
Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4573.
6. Other synthetic studies, see: (a) Micalizino, G. C.; Roush,
W. R. Org. Lett. 2001, 3, 1949; (b) Paquette, L. A.; Peng,
X.; Bonder, D. Org. Lett. 2002, 4, 937; (c) Pihko, P. M.;
Aho, J. E. Org. Lett. 2004, 6, 3849; (d) Peng, X.; Bonder,
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Bonder, D.; Liu, J.; Muller, T.; Paquette, L. A. Org. Lett.
2005, 7, 1813; (f) Halim, R.; Brimble, M. A.; Merten, J.
Org. Lett. 2005, 7, 2659; (g) Halim, R.; Brimble, M. A.;
Merten, J. Org. Biomol. Chem. 2006, 4, 1387; (h) Vellucci,
D.; Rychnovsky, S. D. Org. Lett. 2007, 9, 711; (i) Lotesta,
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O’Connor, P. D.; Knight, C. K.; Friedrich, D.; Peng, X.;
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see: (k) Halim, R.; Brimble, M. A. Org. Biomol. Chem.
2006, 4, 4048.
NOE
H
Me
8
CH3
O
10
TBDPSO
PMBO
Me
O
12
H
S
S
52
Figure 2.
OTBS
TBDPSO
TBSO
PMBO
37
15
12
H
O
O
O
H
16
Hb
CH3
O
17
Ha 18
CH3
7. (a) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997,
1300; (b) Awakura, D.; Fujiwara, K.; Murai, A. Synlett
2000, 1733; (c) Fujiwara, K.; Kobayashi, M.; Yamamoto,
F.; Aki, Y.; Kawamura, M.; Awakura, D.; Amano, S.;
Okano, A.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron
Lett. 2005, 46, 5067.
NOEs
R = -CH2ODMB
19
R
H
H
Figure 3.
8. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737.
9. Fukuyama, T.; Varanesic, B.; Negri, D. P.; Kishi, Y.
Tetrahedron Lett. 1978, 19, 2741.
10. (a) Hayashi, H.; Nakanishi, K.; Brandon, C.; Marmur, J.
J. Am. Chem. Soc. 1973, 95, 8749; (b) Mori, Y.; Takeuchi,
A.; Kageyama, H.; Suzuki, M. Tetrahedron Lett. 1988, 29,
5423; (c) Clive, D. L. J.; Murthy, K. S. K.; Wee, A. G. H.;
Prasad, J. S.; da Silva, G. V. J.; Majewski, M.; Anderson,
NOEs
H3C
H
27
CH3
H3C
28
25
24
O
HO
HO
H
H H
53
Figure 4.

K. Fujiwara et al. / Tetrahedron Letters 48 (2007) 4523–4527
4527
P. C.; Evans, C. F.; Haugen, R. D.; Heerze, L. D.; Barrie,
J. R. J. Am. Chem. Soc. 1990, 112, 3018.
11. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2048.
29. Walker, K. A. M. Tetrahedron Lett. 1977, 18, 4475.
22
30. Selected spectral data of 2: A colorless oil; ½aꢂD +13.2 (c
1
1.43, CHCl3); H NMR (300 MHz, C6D6, C6HD5 as 7.15
ppm) d 0.04 (3H, s), 0.08 (3H, s), 0.13 (3H, s), 0.14 (9H, s),
0.21 (3H, s), 0.28 (9H, s), 0.95 (9H, s), 0.97 (9H, s), 1.21
(9H, s), 1.29 (3H, s), 1.50–1.60 (1H, m), 1.56 (3H, s), 1.70
(1H, dd, J = 3.0, 12.7 Hz), 1.98–2.06 (2H, m), 2.12–2.30
(2H, m), 2.29 (1H, dd, J = 7.6, 12.7 Hz), 3.31–3.40 (1H,
m), 3.36 (3H, s), 3.51 (1H, dt, J = 5.8, 12.7 Hz), 3.70 (1H,
s), 3.86–3.99 (2H, m), 4.09–4.12 (2H, m), 4.21 (1H, dd,
J = 2.6, 5.3 Hz), 4.50 (1H, br t, J = 6.0 Hz), 4.74 (1H, d,
J = 11.2 Hz), 5.02 (1H, d, J = 11.2 Hz), 6.86–6.94 (5H,
m), 7.04–7.29 (6H, m), 7.38 (2H, d, J = 8.8 Hz), 7.77–7.83
(4H, m), 7.87–7.91 (2H, m); 13C NMR (75 Hz, C6D6,
13C12C5D6 as 128.0 ppm) d ꢁ4.7 (CH3), ꢁ4.6 (CH3), ꢁ4.3
(CH3), ꢁ3.3 (CH3), 1.0 (CH3 · 3), 2.6 (CH3 · 3), 18.0 (C),
18.3 (C), 19.4 (C), 23.2 (CH3), 25.9 (CH3 · 3), 26.2
(CH3 · 3), 27.2 (CH3 · 3), 28.3 (CH3), 36.0 (CH2), 36.5
(CH2), 42.9 (CH2), 45.0 (CH2), 52.8 (CH2), 54.8 (CH3),
61.3 (CH2), 70.3 (CH), 70.9 (CH), 74.3 (CH), 74.5 (CH2),
75.1 (C), 85.2 (C), 88.5 (CH), 89.4 (CH), 114.1 (CH · 2),
128.05 (CH · 2), 128.07 (CH · 2), 128.5 (CH · 2), 129.1
(CH · 2), 129.3 (CH · 2), 130.0 (CH · 2), 131.8 (C), 132.9
(CH), 134.3 (C · 2), 135.97 (CH · 2), 136.03 (CH · 2),
141.1 (C), 159.7 (C); IR (film) mmax 3070, 2957, 2935, 2895,
2850, 1612, 1587, 1513, 1472, 1460, 1446, 1428, 1390, 1375,
1361, 1310, 1302, 1251, 1087, 940, 910, 904, 839, 775, 745,
702, 695 cmꢁ1; HR-FDMS calcd for C63H104O10Si5S
[M+]: 1192.6196; found, 1192.6213.
12. Nakata, T.; Oishi, T. Tetrahedron Lett. 1980, 21, 1641.
13. The absolute stereochemistry at C11 of 8 was determined
by new Mosher’s method: Ohtani, I.; Kusumi, T.; Kash-
man, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
14. (a) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B.
Tetrahedron Lett. 1979, 20, 4733; (b) Tomioka, H.; Suzuki,
T.; Nozaki, H.; Oshima, K. Tetrahedron Lett. 1982, 23,
3387.
15. The configuration at C12 of 18 was determined by the
presence of NOE between H10 and C12–CH3 of isopro-
pyridene acetal 52 derived from 18 via 21 (Fig. 2).
16. Ide, M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2491.
17. Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull.
1978, 26, 3743.
18. The use of 2,6-di-tert-butylpyridine was essential to obtain
reproducible result.
19. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155;
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
20. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
21. The optical yield of 11 was determined by HPLC using a
chiral column [Daicel Chiralcel AD, eluent: hexane/2-
propanol (9:1)].
22. The absolute stereochemistry at C18 of 29 was confirmed
by the conversion of 29 to known (3S)-5-(tert-butyldiphen-
ylsilyloxy)-3-methyl-3,5-pentanediol via a two-step pro-
cess [(i) TBDPSCl, imidazole; (ii) H2, Pd/C]. The [a]D
value of the synthetic compound was in good agreement
31. The stereochemistry at C25 of 12 was determined by the
presence of NOE between H21 and C25–CH3.
32. Koch, S. S. C.; Chamberlin, A. R. J. Org. Chem. 1993, 58,
2725.
19
with the reported value {½aꢂD ꢁ7.7 (CHCl3, c 0.975); lit.
33. The stereochemistry at C27 of 3 was confirmed by the
presence of NOEs between C25–CH3 and C27–CH3,
between H27 and H28, and between H28 and H24 in
oxolane 54 derived from 3 through a five-step process [(i)
PPh3, I2, imidazole; (ii) Mg; (iii) DDQ, (iv) m-CPBA
(yielding an almost single diastereomer); (v) CSA.]
(Fig. 4).
20
½aꢂD ꢁ6.61 (CHCl3, c 0.5): Krohn, K.; Meyer, A. Liebigs
Ann. Chem. 1994, 167}.
23. Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
24. Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101,
5848.
25. The absolute stereochemistry at C14 of 33 was determined
by new Mosher’s method. See Ref. 13.
26
34. Selected spectral data of 3: A colorless oil; ½aꢂD ꢁ18.0 (c
26. The presence of the TMS group at C12-oxygen reduced
stereoselectivity of the epoxidation step.
1.70, CHCl3); 1H NMR (300 MHz, CDCl3) d 0.99 (3H, d,
J = 6.8 Hz), 1.21 (3H, s), 1.53–1.60 (2H, m), 1.63–1.65
(1H, m), 1.69 (3H, d, J = 1.0 Hz), 1.71–1.94 (3H, m), 2.53–
2.63 (1H, m), 3.60 (1H, dt, J = 5.8, 11.7 Hz), 3.66 (1H,
ddd, J = 2.4, 5.8, 11.2 Hz), 3.81 (3H, s), 3.85 (2H, m),
3.97–4.03 (1H, m), 4.37 (2H, s), 5.28 (1H, dd, J = 1.3,
9.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz);
13C NMR (75 Hz, CDCl3, 13CDCl3 as 77.0 ppm) d 13.9
(CH3), 22.6 (CH3), 26.9 (CH3), 27.5 (CH2), 29.0 (CH),
37.9 (CH2), 48.3 (CH2), 55.2 (CH3), 65.2 (CH2), 71.0
(CH2), 76.0 (CH2), 78.7 (CH), 83.7 (C), 113.7 (CH · 2),
129.2 (CH · 2), 129.3 (C), 130.7 (C), 135.8 (CH), 159.1
(C); IR (film) mmax 3443, 2959, 2930, 2867, 1614, 1454,
1373, 1302, 1248, 1173, 1070, 1038, 821 cmꢁ1; HR-EIMS
calcd for C21H32O4 [M+]: 348.2301; found, 348.2300.
27. The configurations at C15 and C16 of oxolane 36 were
confirmed by the presence of NOEs between H15 and
C12–CH3, between H15 and H17a, between H17a and
C18–CH3, and between H16 and H19 in 37 (Fig. 3).
28. We found that a primary alkyl DMB ether was readily
removed on treatment with TMSOTf/2,6-lutidine. This
phenomenon was helpful for selective detachment of the
DMB group of 37 in the presence of the PMB ether at
C11. On the other hand, detachment of a DMB group
from 29 during TMS ether formation was avoided by
lowering the reaction temperature (Scheme 3). cf. Oriy-
ama, T.; Yatabe, K.; Kawada, Y.; Koga, G. Synlett 1995,
45.