Computer-assisted design and lactonization of model seco-acid derivatives of lankanolide

Article abstract of DOI:10.1016/j.tet.2004.03.061

In some cases, seco-acid derivatives (a precursor of macrolactone) did not cyclize to form the corresponding macrolactone. To design easily cyclizable seco-acid derivatives of lanaknolide, the conformation of several model seco-acids was calculated, and l

Full text of DOI:10.1016/j.tet.2004.03.061

Tetrahedron 60 (2004) 4693–4704
Computer-assisted design and lactonization of model seco-acid
derivatives of lankanolideq
*
Tatsuo Hamada, Mitsugu Kiyokawa, Yukinari Kobayashi, Toshikazu Yoshioka, Junichiro Sano
and Osamu Yonemitsu†
Faculty of Pharmaceutical Sciences, Hokkaido University, N-12, W-6, KITAKU, Sapporo 060-0812, Japan
Received 22 May 2003; revised 21 March 2004; accepted 22 March 2004
Abstract—In some cases, seco-acid derivatives (a precursor of macrolactone) did not cyclize to form the corresponding macrolactone. To
design easily cyclizable seco-acid derivatives of lanaknolide, the conformation of several model seco-acids was calculated, and lactonization
experiments of the seco-acids prepared from oleandomycin were carried out to elucidate the efficiency of the cyclization of the model seco-
acid. The easily cyclable seco-acid was designed to be C8 exomethylene derivative of lankanolide seco-acid. On the other hand, seco-acid
derivative having tertiary alcohol at C8 was predicted not to cyclize to form macrolactone.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives.5 To avoid such a case, we decided to design the
target seco-acid derivatives by computer-aided simulation
before starting the synthesis.6 In our design, there are two
routes depending on whether before cyclization, C8 is
quaternalized (route a) or after cyclization, an asymmetric
center at C8 is introduced (route b). Route a is via seco-acid
II which has tertiary alcohol at C8 position. In route b,
macrolactone IV is oxidized to prepare a tertiary alcohol at
C8 after cyclization. The critical point of these two routes
will be the reactivity of seco-acids II and V Scheme 1. To
predict the reactivity of seco-acids II and V, first, we
calculated the conformation of the methyl ester of model
seco-acid derivatives (4, 6 and 8) corresponding to seco-
acids II and V, and the lactones (3, 5, and 7) (Fig. 2).
The target molecule, lankanolide 2, is the aglicone of
14-membered macrolide lankamycin 1. Lankamycin was
isolated in 1960 by Gaumann et al.,2 and the relative stereo-
structure of the macrolide was determined in 1972 by
Keller-Schlierlein et al.3 Since then, there has appeared no
report of the total synthesis of this macrolide, while
synthetic efforts have been carried out.4 We are interested
in the effect of the structure of the seco-acid derivative on
the efficiency of macrolactonization (Fig. 1). In some cases,
seco-acid derivatives did not cyclize to give macrolactone
2. Results and discussions
2.1. Computer-assisted design of model seco-acid
Recently, Goto et al. developed a conformational search
method of chain compounds by stepwise bond rotation
(conflex).7 First, we calculated the conformations of seco-
acid derivatives (4, 6, and 8) by using ‘CONFLEX’ and the
obtained conformers were classified to conformation cluster
(experimental detail was shown in Section 3.4). Similar
conformation (differences of all dihedral angle to be
compared are less than 108) is classified in one cluster.
The similarity of the clusters between seco-acid derivative
and the corresponding lactone was also calculated, and the
similarity was shown as cluster distance. The more similar
the conformation of the cluster to be compared is, the
Figure 1. Lankamycin and lankanolide. Lankamycin (1): R1¼D-chalcose,
R2¼acetylarcanose. Lankanolide (2): R1¼H, R2¼H.
q See Ref. 1.
Keywords: Conformation calculation; seco-Acid; Lactonization;
Lankanolide.
*
Corresponding author. Tel./fax: þ81-11-706-3980;
e-mail address: hamada@pharm.hokudai.ac.jp
Present address: Department of Chemistry, Okayama University of
Science, Okayama 700-0005, Japan.
†
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.061

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T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
Scheme 1. Retro synthetic analysis of lankanolide.
Figure 2. Model seco-acids and lactones for conformation calculation.
smaller the conformation distance is.8 Obtained number of
conformers having more than 0.01% population are
shown below: 120 for 4, 256 for 6, 153 for 8, 2 for 3, 4
for 5, 11 for 7.
conformers generated by conformation search) and Table 2
(cluster distance; cluster similarity between starting seco-
acid and the corresponding cyclized lactone) and Figure 3.
As shown in Figure 3, the simulated conformation of the
methyl ester of seco-acid 4 showed a conformation cluster
(#2, 15.2%) of the seco-acid is similar conformation to the
The results were shown in Table 1 (clustering results of
corresponding cluster of lactone
3 (conformation
distance¼8.7).8,9 On the other hand, the calculated confor-
mation of diacetonide seco-acid 6 showed no similar
conformation to the major cluster corresponding to lactone
5. It is well known that the 6-membered ketal of anti-1,3-
diol prefers twist-boat type,10 and the most preferable
conformer of 6-membered ketal of anti-1,3-diol (C9, C11)
of model seco-acid 6 was also twist-boat (Fig. 3). However,
most of the conformations of the corresponding lactone 5
was chair type (Fig. 3). Therefore, twist-boat conformer has
to change to the more unstable chair conformer before
cyclization. However, in the case of seco-acid 6, there is a
cluster (#11, population 1.5%) close to the lactone 5,
although population is not high.9 The simulated confor-
mation of 8 methyl ester also did not contain a similar
conformation to the corresponding lactone 7 (conformation
distance between the closest conformation of 8 was 49.7).
Most of the conformation of model compound 8 is locked as
shown in Figure 3, mainly becouse of hydrogen bonding
between the tertiary alcohol at C8 and ether oxygen of
6-membered ketal of C3 and C5 diol. Because of the locked
Table 1. Major conformation clusters of model seco-acids (4, 6, and 8) and
corresponding lactones (3, 5, and 7)
Sizea
Popb (%)
Size
Pop (%)
Rank
1
2
3
4
4
6
3
5
126
57
29
62
64
70.78
15.18
3.21
2.90
2.77
4
2
99.99
0.01
5
Rank
1
2
3
4
82
40
19
28
4
56.2
16.1
4.0
3.4
1.7
5
5
99.7
0.3
5
11
Rank
1
14
1.5
8
7
23
2
99.2
0.8
32
27
99.9
0.1
2
a
Number of conformers comprising a cluster.
Combined percentage population of the component conformers.
b

T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
Table 2. Cluster distance analysis of the model seco-acids and the corresponding lactones
4695
4
1
2
3
4
5
6
7
8
9
10
3
1
2
72.13
81.25
1
8.72
42.25
2
79.26
86.16
3
65.34
72.81
4
84.77
90.3
5
62.89
76.95
6
64.92
75.59
7
47.24
62.56
8
83.94
91.69
9
82.59
87.34
10
6
8
11
5
1
2
79.33
73.48
1
71.62
89.92
2
65.82
64.46
72.08
48.8
47.39
11.73
79.47
96.1
73.81
52.17
82.27
69.05
86.14
79.96
83.05
81.86
6.44
33.51
7
1
49.77
48.69
Close distances (less than 10) are printed in bold letters.
Figure 3. Conformational distance between the cluster of lactone (3, 5 and 7) and the corresponding seco-acid (4, 6 and 8).
structure, the reaction point (alcohol at C13 and terminal
carboxylic acid) can not approach each other. This result
suggests that seco-acid 4 having a similar conformation to
the corresponding lactone will easily cyclize to form
macrolactone.9 The diacetonide seco-acid 6 will cyclize
slowly in low yield. The seco-acid having a tertiary alcohol
at C8 (8) can be predicted not to cyclize because
unfavorable conformation to cyclize is locked by hydrogen
bonding. To test the predicted reactivity of these three types
of seco-acids, we synthesized several model seco-acids, and
performed cyclization experiments.
dimethylacetal and cyclization of iodohydrin with
NaHCO3. The epoxide of 10 was deoxygenated to form
exo-olefin 11, followed by 1,2-reduction of enone to give
diol 12 as a single diastereomer. Acetalization of diol of 12
and hydrolysis of lactone gave seco-acid 14. seco-Acid 20
and 23 were synthesized by a similar method. Acetalization
of 9 and epoxide formation gave 16 and deoxigenation of 16
gave 17, then 1,2-reduction afforded diol 18 as a single
isomer. The diol of 18 was protected as an acetonide and
hydrolyzed with NaOH to form seco-acid 20. Similar
treatment of 18 with mesitaldehyde dimethylacetal, and
hydrolysis of lactone gave seco-acid 23. seco-Acid 32 was
also synthesized starting from 9 as shown in Scheme 3. The
diol of 9 was protected as a mesitilidene acetal, following
reduction of ketone, and the resulting diol was again
protected as a mesitilidene acetal to give 28. The lactone
and epoxide were reduced with LAH to form a triol. The
primary alcohol of the triol was protected as a TBDMS
2.2. Synthesis of model seco-acids (14, 20, 23, and 32)
seco-Acids (14, 20, 23, and 32) were prepared starting from
the known intermediate 9 reported by Paterson et al.11 as
shown in Schemes 2 and 3. The iodide 9 was converted to
epoxy-ketone 10 via acetalization with mesitaldehyde

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T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
Scheme 2. Preparation of model seco-acid derivatives 14, 20 and 23. Reagents and conditions: (a) MesCH(OMe)2, CSA, CH2Cl2, rt, 6 h; (b) 8% aq-NaHCO3,
THF, rt, 20 min; (c) CrCl2, acetone–H2O (2:1), 0 8C, 3 h; (d) BaBH4, CeCl3,THF, 225 8C, 4.5 h; (e) MesCH(OMe)2, CSA, rt, 24 h; (f) 5 N-NaOH, DMSO,
90 8C, 5 h; (g) Me3SiCHN2, benene, rt, 1 h; (h) Me2C(OMe)2, PPTS, CH2Cl2, rt, 1 h; (i) 10% aq-NaHCO3, THF, rt, 40 min; (j) CrCl2, acetone–H2O (2:1), 0 8C,
30 min; (k) NaBH4, CeCl3, 225 8C, 4.5 h; (l) 2-Methoxypropene, PPTS, CH2Cl2, 0 8C, 1.25 h; (m) 5 N-NaOH, DMSO, 90 8C, 7 h; (n) Me3SiCHN2, benzene,
rt, 45 min; (o) MesCH(OMe)2, CH2Cl2, CSA, rt, 6 h; (p) 5 N-NaOH, DMSO, 90 8C, 12 h; (q) Me3SiCHN2, benzene, rt, 45 min.
ether, and the secondary alcohol was acetylated to give 29.
Deprotection of TBDMS and Jones oxidation followed by
deacetylation gave seco-acid 32.
and 22 in high yield, even under the normal concentration
conditions. On the other hand, seco-acid 20 (diacetonide)
cyclized sluggishly to form lactone 19 in low yield even
under the high dilution condition. seco-Acid 32 did not give
34 at all even under the high-dilution condition (Table 3 and
Scheme 4).
2.3. Cyclization experiments of the model seco-acids
seco-Acids (14, 20, 23, and 32) were subjected to
macrolactonization. The results of cyclization experiments
are shown in Table 3 and Scheme 4. As we predicted, seco-
acid 14 and 23 cyclize smoothly to give macrolactones 13
2.4. Conclusion
The compatibility between computer-simulated reactivity

T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
4697
Scheme 3. Preparation of seco-acid derivative 32. Reagents and conditions: (a) NaBH4, i-PrOH-AcOEt (2:1), rt, 20 min. (b) MesCH(OMe)2, CSA, CH2Cl2, rt,
5 h. (c) LiAlH4, Et2O, 30 8C, 2 h. (d) TBDMSCl, Et3N, DMAP, CH2Cl2, rt, 24 h. (e) Ac2O, Et3N, DMAP, CH2Cl2, rt, 33 h;. (f) n-Bu4NF, THF, rt, 3.5 h.
(g) Jones reagent, acetone, 230 8C, 5 h. (h) 15% NaOH, MeOH, rt, 24 h. (i) Me3SiCHN2, benzene, rt, 1 h.
and chemical reactivity is so important that the computer-
simulated conformation analysis may predict the reactivity
of intramolecular cyclization, and the most preferable
model seco-acid to synthesize lankanolide is seco-acid 23.
In some cases, computer-assisted conformation analysis of
model seco-acid may complement synthetic design. We are
continuing research along this line, and we reported a
successful example of total synthesis of lankanolide 2 via
the seco-acid designed according to the model seco-acid
23.12
were measured with a JASCO DIP-370 polarimeter, and
P-1030 polarimeter. IR spectra were recorded with a JASO
FT/IR-5300 spectorometer. Proton and carbon NMR were
recorded with JEOL-EX-270, JEOL-EX-400 and Bruker
ARX-500 spectrometers, using tetramethylsilane as an
internal standard. Mass spectra were recorded with JEOL
JMS-700 TZ and JEOL HMS-HX1100. Column chroma-
tographies were performed on Kanto silicagel 60N (spheri-
cal, neutral; 40–100 mm). Merk precoated silicagel 60F254
plates (0.25 mm thickness) were used for analytical thin-
layer chromatography.
3. Experimental
3.2. Preparation of seco-acids 14, 20, and 33
3.1. General procedures
3.2.1. 3,5-O-(2,4,6-Trimethylbenzylidene)-oleandonolide
(10). A solution of 9 (264 mg, 0.51 mmol) and mesitalde-
hyde dimethylacetal (63 mg, 1.02 mmo0l) and camphor-
sulfonic acid (3 mg, 13 mmol) in CH2Cl2 (4 ml) was stirred
for 6 h and then treated with sat. NaHCO3. The mixture was
extracted with CH2Cl2 and the combined extract was
washed with brine, dried over Na2SO4, and evaporated to
All reactions were carried out under argon atmosphere
unless otherwise specified. CH2Cl2, DMSO and triethyl-
amine were distilled from CaCl2 and stored on molecular
sieves. Ether and THF were distilled from sodium-
benzophenone ketyl, and used freshly. Optical rotations
Table 3. Cyclization reactions of several seco-acids
seco-Acid (mM)
Cyclization methoda
DMAP (mol equiv.)
Reaction temp (8C)
Reaction time (h)
Yield (%)
14 (1.0)
14 (6.6)
23 (1.0)
23 (1.0)
20 (1.0)
20 (1.0)
32 (1.0)
A
B
A
B
A
B
A
2.5
3
2.5
3
2.5
2.5
2.5
130
rt
130
rt
130
rt
130
43
3
11
3
43
43
43
97
82
96
81
15
0
0
a
A; High-dilution condition: To a 6 mM toluene solution of DMAP in toluene, was added slowly a 2 mM toluene solution of the mixed anhydride prepared
from seco-acid and 2,4,6-trichlorbenzoyl chloride. B: Normal condition: DMAP was added to a 10 mM toluene solution of the mixed unhydride.

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T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
Scheme 4. Effect of C8 functional groups on macrolactonization. Reagents and conditions: (a) to a solution of DMAP was added slowly a dilute solution of the
mixed anhydride prepared from seco-acid (14, 20, 23 and 32) and 2,4,6-trichlorobenzoyl chloride.
dryness in vacuo. The residue was chromatographed on a
silicagel column eluting with hexane and ethyl acetate
(3:1) to give iodohydrin (187 mg, 57%) as an amorphous
solid.
mixture was extracted with CH2Cl2 and the combined
extract was washed with brine and dried over Na2SO4 and
concentrated to dryness in vacuo. The residue was
chromatographed on a silicagel column eluting with hexane
and ethyl acetate (3:1) to give 10 (118 mg, quant.) as an
amorphous solid.
[a]2D2¼246.08 (c¼0.98, CHCl3). 1H NMR (500 MHz,
CDCl3) d 6.81 (2H, s), 5.80 (1H, s), 5.63 (1H, dq, J¼2.0,
6.9 Hz), 3.93 (1H, dd, J¼10.3, 3.4 Hz), 3.84 (1H, dd, J¼6.0,
1.3 Hz), 3.80 (1H, s), 3.69 (1H, t, J¼6.0 Hz), 3.59 (1H, dd,
J¼5.2, 0.9 Hz), 3.58 (1H, t, J¼6.5 Hz), 3.53 (1H, d,
J¼10.3 Hz), 3.42 (1H, d, J¼10.3 Hz), 3.12 (1H, q,
J¼6.9 Hz), 3.11 (1H, d, J¼3.0 Hz), 2.84 (1H, dq, J¼10.3,
6.7 Hz), 2.57 (1H, m), 2.45 (6H, s), 2.23 (3H, s), 2.21 (1H,
m), 2.01 (1H, q, J¼6.5 Hz), 1.84 (1H, d, J¼14.5 Hz), 1.82
(1H, dd, J¼14.5, 6.1 Hz), 1.70–1.58 (2H, m), 1.25 (3H, d,
J¼6.7 Hz), 1.16 (3H, d, J¼6.6 Hz), 1.36 (3H, d, J¼6.7 Hz),
1.08 (3H, d, J¼7.0 Hz), 1.06 (3H, d, J¼7.4 Hz), 0.93 (3H, d,
J¼7.3 Hz). MS (EI) m/z 644 (Mþ). HRMS (EI) m/z Calcd
for C30H45O7I (Mþ) 644.2228, found 644.2205.
1
[a]2D5¼252.08 (c¼0.77, CHCl3). IR (neat) 1740 cm21. H
NMR (400 MHz, C6D6) d 6.77 (2H, s), 6.06 (1H, dq, J¼1.0,
0.6 Hz), 5.98 (1H, s), 4.46 (1H, dq, J¼2.0, 6.4 Hz), 4.01
(1H, dd, J¼1.5, 7.3 Hz), 3.89 (1H, dd, J¼1.5, 10.7 Hz), 2.91
(1H, d, J¼4.9, 6.8 Hz), 2.77 (1H, d, J¼4.4 Hz), 2.66 (1H,
dd, J¼2.0, 6.4 Hz), 2.55 (6H, s), 2.29–2.34 (1H, m), 2.30
(1H, d, J¼3.9 Hz), 2.13 (3H, s), 1.95 (1H, dd, J¼12.2,
15.6 Hz), 1.77–1.88 (1H, m), 1.47–1.55 (1H, m), 1.42 (1H,
dd, J¼2.0, 15.6 Hz), 1.37 (3H, d, J¼6.8 Hz), 1.36 (3H, d,
J¼6.8 Hz), 1.20 (3H, d, J¼6.3 Hz), 1.10 (3H, d, J¼6.3 Hz),
1.10 (3H, d, J¼6.3 Hz), 1.05 (3H, d, J¼7.3 Hz), 0.76 (3H,
d, J¼6.8 Hz). 13C NMR (100.4 Hz, C6D6) d 204.9,
173.9, 137.9, 137.1, 132.1, 130.1, 127.9, 103.9, 85.2, 70.1,
69.9, 63.5, 47.2, 46.5, 41.7, 33.3, 32.3, 21.0, 20.9, 18.4,
16.6, 13.3, 9.7, 6.4. MS (EI) m/z 516 (Mþ). HRMS
(EI) m/z Calcd for C30H44O7 (Mþ) 516.3087, found
516.3068.
A cooled (0 8C) mixture of the above iodohydrin (151.2 mg,
0.23 mmol) in THF (25 ml) and 8% aq. NaHCO3 (25 ml)
was stirred for 20 min and then treated with phosphate
buffer (pH 6.86, 25 ml). After stirring for further 5 min, the

T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
4699
3.2.2. 8,8a-Deoxa-3,5-O-(2,4,6-trimethylbenzylidene)-
oleandonolide (11). To a cooled (0 8C) solution of 10
(428 mg, 0.83 mmol) in acetone (7 ml) was added dropwise
CrCl2 (306 mg, 2.49 mmol) in H2O 3.5 ml, and the solution
was treated with sat. NaHCO3, and extracted with ether. The
combined extract was washed with brine and dried over
Na2SO4 and concentrated to dryness in vacuo. The residue
was chromatographed on a silicagel column eluting with
hexane and ethyl acetate to give exo-olefin 11 (266 mg,
64%) as an amorphous solid.
give dimesitilidene acetal 13 (73 mg, 86%) as an amorphous
solid.
[a]2D2¼267.48 (c¼1.02, CHCl3). IR (neat) 1720, 1630,
1630 cm21 1H NMR (400 MHz, C6C6) d 6.80 (4H, d,
.
10.0 Hz), 6.48 (1H, s), 6.15 (1H, s), 5.86 (1H, dq, J¼0.9,
6.6 Hz), 5.73 (1H, s), 5.28 (1H,s), 4.43 (1H, dd, J¼2.0,
7.0 Hz), 4.36 (1H, br. s). 3.96 (1H, d, J¼10.9 Hz), 3.63 (1H,
dd, J¼1.0, 10.0 Hz), 2.88 (6H, s), 2.84–2.90 (1H, m), 2.73–
2.78 (1H, s), 2.57 (1H,s), 2.13 (6H, d, J¼6.8 Hz), 1.88–2.01
(2H, m), 1.92 (1H, dd, J¼17.5, 12.0 Hz), 1.69 (1H, br d,
J¼17.5 Hz), 1.50–1.56 (1H, m), 1.40 (3H, d, J¼6.6 Hz),
1.39 (3H, d, J¼6.8 Hz), 1.33 (3H, d, J¼6.6 Hz), 1.23 (3H, d,
J¼7.1 Hz), 0.91 (3H, d, J¼7.3 Hz), 0.77 (3H, d, J¼7.3 Hz).
MS (EI) m/z (Mþ) 630. HRMS (EI) m/z Calcd for C40H56O6
(Mþ) 632.4077, found 632.4080.
[a]2D2¼255.78 (c¼0.98, CHCl3). IR (neat) 1740, 1702,
1620 cm21. 1H NMR (400 MHz, C6C6) d 6.78 (2H, s), 6.05
(1H, s), 5.95 (1H, s), 5.76 (1H, dq, J¼1.0, 6.4 Hz), 5.13 (1H,
s), 4.03 (1H, dd, J¼1.0, 6.4 Hz), 3.80 (1H, dd, J¼5.4,
8.8 Hz), 3.68 (1H, dd, J¼1.5, 10.8 Hz), 2.89 (1H, dq, J¼1.0,
6.8 Hz), 2.82 (1H, dq, J¼6.4, 10.8 Hz), 2.71 (1H, d,
J¼5.4 Hz), 2.56 (6H, s), 2.48–2.56 (1H, m), 2.15 (3H,s),
2.13–2.18 (1H, m), 1.98 (1H,dd, J¼6.8, 13.7 Hz), 1.91 (1H,
dd, J¼2.4, 18.1 Hz), 1.38–1.47 (1H, m), 1.34 (3H, d,
J¼6.8 Hz), 1.29 (3H, d, J¼6.4 Hz), 1.17 (3h, d, 6.4 Hz),
1.15 (3H, d, J¼7, 3 Hz), 1.06 (3H, d, J¼6.4 Hz), 0.72 (3H,
d, J¼7.3 Hz). 13C NMR (100.4 MHz, C6D6) d 204.79,
174.5, 146.8, 138.0, 137.1, 131.9, 130.2, 127.9, 121.0,
104.0, 85.2, 80.8, 70.6, 43.6, 42.6, 41.6, 34.0, 33.1, 33.0,
21.0, 20.9, 18.5, 16.6, 13.3, 9.8, 9.0, 6.6. MS (EI) m/z 500
(Mþ). HRMS (EI) m/z Calcd for C30H44O6 (Mþ) 500.3184,
found 500.3137.
3.2.5. (9R)-3,9:9,11-Bis-O-(2,4,6-trimethylbenzylidene)-
8,8a-deoxa-9-dihydrooleandonolide seco-acid (14). A
solution of 13 (175 mg, 0.28 mmol)and 5-N NaOH
(1.6 ml, 8 mmol) in DMSO (3.8 ml)was stirred for 5 h at
90 8C and then cooled to room temperature and extracted
with ether. The aqueous layer was neutralized with 10% aq.
HCl (6 ml). The mixture was extracted with ether and the
combined extract was washed with brine and dried over
Na2SO4 and evaporated to dryness in vacuo. The residue
was chromatographed on a silicagel column eluted with
hexane and ethyl acetate (1:2) to give seco-acid 14 (154 mg,
86%) as an amorphous solid. Because NMR of the seco-acid
showed peak broadening, the seco-acid was characterized as
its methyl ester 15.
3.2.3. (9R)-3,5-O-(2,4,6-Trimethylbenzylidene)-8,8a-
deoxa-9-dehydro-oleandonolide (12). To
a
cooled
(225 8C) solution of 11 (266 mg, 0.53 mmol) in THF
(8 ml) was added CeCl3.H2O (102 mg, 0.27 mmol) and after
stirring for 30 min, NaBH4 38 mg, (1.00 mmol) was added
to the suspension and the mixture was stirred for 4.5 h at
225 8C and treated with sat. NH4Cl and extracted with
ether. The combined extract was washed with brine and
dried over Na2SO4 and evaporated to dryness in vacuo. The
residue was chromatographed on a silicagel column eluting
with hexane and ethyl acetate (3:1) to afford diol 12
(230 mg, 91%) as an amorphous solid.
[a]2D3¼257.98 (c¼0.50, CHCl3). IR (neat) 1720, 1630,
1620 cm21. MS (EI) m/z 650 (Mþ). HRMS (EI) m/z Calcd
for C40H58O7 (Mþ) 640.4183, found 650.4166.
3.2.6. (9R)-3,5:9,11-Bis-O-(2,4,6-trimethylbenzylidene)-
8,8a-deoxa-9-dihydrooleandonolide seco-acid methyl
ester (15). To a solution of 14 (12.0 mg, 1.5 mmol) in
benzene 1.0 ml) was added MeOH (200 ml) and 10%
hexane solution of trimethylsilyldiazomethane (200 ml,
176 mmol) and the solution was stirred for 1 h and then
treated with acetic acid and the solution was diluted with
ether and washed with sat. NaHCO3 and brine and dried
over Na2SO4 and concentrated to dryness in vacuo. The
residue was chromatographed on a silicagel column eluting
with hexane and ethyl acetate (4:1) to give methyl ester 15
(11.4 mg, 93%) as an amorphous solid.
[a]2D3¼228.08 (c¼0.98, CHCl3). IR (neat) 1730, 1660,
1620 cm21. 1H NMR (400 MHz, C6C6) d 6.80 (1H,s), 6.02
(1H, s), 5.64–5.67 (1H, m), 5.61 (1H, s), 5.14 (1H, s), 4.35
(1H, dd, J¼1.5, 114 Hz), 3.75–3.82 (3H, m), 3.56–3.62
(2H, m), 2.78–2.97 (3H, m), 2.59 (6H, s), 2.15 (1H, s),
1.59–1.90 (4H, m), 1.34 (3H, d, J¼7.0 Hz), 1.31 (3H, d,
J¼6.6 Hz), 1.20 (3H, d, J¼7.3 Hz), 1.14 (3H, d, J¼7.0 Hz),
1.04 (3H, d, J¼6.6 Hz), 0.68 (3H, d, J¼7.0 Hz). MS (EI)
m/z 502 (Mþ); HRMS (EI) m/z Calcd for C30H46O6 (Mþ)
502.3230, found 502.3322.
1H NMR (400 MHz, C6C6) d 6.73 (4H, m) 6.15 (1H,s), 5.79
(1H, s), 5.11 (1H,s), 4.29 (1H, br s), 4.20 (1H, dd, J¼2.0,
10.3 Hz), 3.98 (1H, dq, J¼2.1, 6.6 Hz), 3.93 (1H, dd, J¼2.1,
10.1 Hz), 3.35 (3H, s), 3.17 (1H, dd, J¼2.1, 9.7 Hz), 3.00
(1H, br dd, J¼3.0, 15.0 Hz), 2.87 (1H, dq, J¼6.8, 10.1 Hz),
2.54 (3H, s), 2.39 (3H, s), 2.19 (3H, s), 2.10–2.04 (1H, m),
1.00–2.04 (1H, m), 1.78–1.89 (3h, M), 1.32 (3h, D,
J¼6.8 Hz), 1.28 (3H, d, J¼6.8 Hz), 1.14 (3H, d, J¼6.8 Hz),
1.00 (3H, d, J¼6.6 Hz), 0.80 (3H, d, J¼6.8 Hz), 0.66 (3H, d,
J¼7.1 Hz).
3.2.4. (9R)-3,5:9,11-Bis-O-(2,4,6-trimethylbenzylidene)-
8,8a-deoxa-9-dihydro-oleandonolide (13). A solution of
the above diol 12 (72 mg, 0.14 mmol) and mesitaldehyde
dimethylacetal (82 mg, 0.92 mmol) and camphorsulfonic
acid (3 mg) was stirred for 24 h and then treated with
sat. NaHCO3. The mixture was extracted with ether and
the extract was washed with brine and dried over Na2SO4
and evaporated to dryness in vacuo. The residue was
chromatographed on a silicagel column eluting with
benzene hexane (1:1) to hexane and ethyl acetate (9:1) to
3.2.7. 3,5-O-(Isopropylidene)-oleandonolide (16). Com-
pound 16 was prepared following the known method by
Paterson et al.11 To a solution of 9 (130 mg, 0.273 mmol)

4700
T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
and 2,2-dimethoxpropane (6 ml, 48.9 mmol) in CH2Cl2
(10 ml) was added PPTS (7 mg, 0.028 mmol) at rt. The
solution was stirred for 1 h at rt, then treated with phosphate
buffer (pH 7.0), and extracted with CH2Cl2. The combined
extract was concentrated to dryness in vacuo. The residue
was chromatographed on a silicagel column eluting with
hexane and ethyl acetate (2:1) to give acetonide (105 mg,
75%). To a cooled (0 8C) solution of the acetonide (460 mg,
0.830 mol) in THF (75 ml) was added 10% aq.NaHCO3
(75 ml), and the mixture was stirred for 40 min, then treated
with phosphate buffer (pH7.0). The mixture was extracted
with CH2Cl2 and the combined extract was dried over
MgSO4 and concentrated to dryness. The residue was
chromatographed on a silicagel column eluting with hexane
and ethyl acetate (2:1) to give 16 (355 mg, quantitative
yield) as an amorphous solid.
dd, J¼6.6, 1.0 Hz), 4.00 (1H, br. s), 3.62 (1H, dd, J¼10.5,
1.0 Hz), 3.46 (1H, m), 3.37 (1H, d, J¼8.0 Hz), 3.03 (1H, d,
J¼4.0 Hz), 2.63 (1H, dd, J¼11.5, 6.8 Hz), 2.50 (1H, m),
2.04 (1H, m), 1.97 (1H, dd, J¼17.0, 11.5 Hz), 1.50–1.61
(2H, m), 1.44 (6H, s), 1.25 (3H, d, J¼6.8 Hz), 1.12 (3H, d,
J¼6.8 Hz), 1.03 (3H, d, J¼7.3 Hz), 0.98 (3H, d, J¼6.8 Hz),
0.98 (3H, d, J¼7.3 Hz). 13C NMR (100.4 MHz, C6D6), d
175.8, 147.6, 109.2, 100.6, 72.972.5, 72.1, 69.5, 42.6, 41.6,
35.3, 34.6, 32.4, 32.0, 29.7, 19.9, 18.7, 16.3, 13.2, 9.6, 8.7,
7.7. MS (EI) m/z 412 (Mþ). HRMS (EI) m/z Calcd for
C23H40O6 (Mþ) 412.2825, found 412.2838.
3.2.10. (9R)-3,5:9,11-Bis-O-isopropylidene-8,8a-deoxa-9-
dihydrooleandonolide (19). A solution of the above diol 18
(112 mg, 0.27 mmol) in CH2Cl2 was added 2-methoxy-
propene (80 ml, 0.81 mmol) and PPTS (20 mg, 85 mmol) at
0 8C and the solution was stirred for 1.25 h and then treated
with sat. NaHCO3 and extracted with ether. The combined
extract was washed with brine and dried over Na2SO4 and
concentrated to dryness in vacuo. The residue was
chromatographed on a silicagel column eluting with hexane
ethyl acetate (8:1) to give diacetonide 19 (85 mg, 70%) as
an amorphous solid.
[a]2D3¼250.18 (c¼1.20, CHCl3). 1H NMR (270 MHz,
CDCl3) d 5.76 (1H, dq, J¼1.2, 6.6 Hz), 4.36 (1H, m),
4.01 (1H, dd, J¼1.3, 6.9 Hz), 3.74 (1H, J¼1.3, 10.7 Hz),
3.10 (1H, d, J¼4.2 Hz), 3.03 (1H, dq, J¼1.8, 6.5 Hz), 2.96
(1H, d, J¼4.2 Hz), 2.75 (1H, dq, J¼6.6, 10.6 Hz), 2.41 (1H,
d, J¼5.5 Hz), 2.24 (1H. dd, J¼12.4, 15.7 Hz), 1.96–2.08
(2H, m), 1.65 (1H, m), 1.42 (3H, s), 1.41 (3H, s), 1.28 (3H,
d, J¼6.6 Hz), 1.16 (3H, d, J¼6.5 Hz), 1.07 (3H, d,
J¼6.5 Hz), 1.04 (3H, d, J¼6.5 Hz), 1.03 (3H, d,
J¼7.2 Hz), 1.01 (3H, d, J¼7.2 Hz).
[a]1D9¼226.68 (c¼0.23, CHCl3). IR (neat) 1730, 1640,
1620 cm21. 1H NMR (400 MHz, C6D6) d 5.62 (1H, s), 5.47
(1H, dq, J¼1.0, 6.8 Hz), 5.22 (1H, br. s), 4.24 (1H, br. s),
4.19 (1H, dd, J¼1.5, 6.4 Hz), 3.57 (1H, dd, J¼1.0, 10.7 Hz),
3.43 (1H, d, J¼9.3 Hz), 2.68 (1H, ddq, J¼6.8, 2.5, 10.7 Hz),
2.49–2.56 (1H, m), 2.11 (1h, DD, J¼6.5, 13.5 Hz), 1.94–
1s.96 (2H, m), 1.69 (1H, dd, J¼6.5, 13.5 Hz), 1.49–1.53
(1H, m), 1.45 (3H, s), 1.44 (3H, s), 1.40 (3H.s), 1.29 (3H, s),
1.22 (3H, d, J¼6.8 Hz), 1.13 (3H, d, J¼6.8 Hz), 1.10 (3H, d,
J¼6.8 Hz), 1.08 (3H, d, J¼6.8 Hz), 1.04, (3H, d, J¼6.4 Hz),
0.93 (3H, d, 6.7 Hz). 13C NMR (100.4 Hz, C6D6) d 174.0,
144.8, 113.9, 100.8, 100.2, 80.8, 77.2, 71.9, 69.6, 68.5, 41.0,
40.2, 33.7, 32.5, 32.4, 31.0, 29.8, 29.0, 26.8, 19.7, 18.6,
16.2, 13.0, 11.7, 7.8, 7.4. MS (EI) m/z 452 (Mþ). HRMS
(EI) m/z Calcd for C26H44O6 (Mþ) 452.3138, found
452.3120.
3.2.8. 8,8a-Deoxa-3,5-O-(2,4,6-isopropylidene)-oleando-
nolide (17). To a cooled (0 8C) solution of 16 (2.03g,
4.76 mmol) in acetone (40 ml) was added dropwise CrCl2
(1.76 g, 14.28 mmol) in H2O (20 ml). After stirring for
30 min, the solution was treated with sat. NaHCO3,
extracted with brine and dried over Na2SO4 and evaporated
to dryness in vacuo. The residue was chromatographed on
a silicagel column eluting with hexane and ethyl acetate
to give exo-olefin 17 (1.60 g, 82%) as an amorphous
solid.
[a]D24¼230.98 (c¼1.00, CHCl3). IR (neat) 1720 cm2 1
H
NMR (400 MHz, C6C6) d 6.00 (1H,s), 5.74 (1H, dq, J¼1.5,
6.00 Hz), 5.08 (1H, s), 4.10 (1H, dd, J¼1.5, 6.2 Hz), 3.72–
3.79 (2H, m), 2.72–2.90 (3, m), 1.79–2.36 (5H, m), 1.33
(3H, d, J¼6.6 Hz), 1.24 (6H, s), 1.17 (3H, d, J¼6.6 Hz),
1.15 (3H, d, J¼6.6 Hz), 1.10 (3H, d, J¼6.2 Hz), 0.69 (3, d,
J¼7.0 Hz). MS (EI) m/z 410 (Mþ). IHRMS (EI) m/z Calcd
for C23H38O6 (Mþ) 410.2669, found 410.2643.
3.2.11. (9R)-3,5:9,11-Bis-O-isopropilidene-8,8a-deoxa-9-
dihydrooleandonolide seco-acid (20). A solution of the
above diacetonide lactone 19 (121 mg, 0.29 mmol) and
5 N-NaOH (1.7 ml) in DMSO (3.9 ml) was stirred for 7 h at
90 8C. After cooling to room temperature, the solution was
extracted with ether. The combined organic layer was
washed with sat. NaHCO3 and water and the combined
aqueous layer was neutralized with 10% HCl and extracted
with ether and the extract was washed with brine and dried
over Na2SO4 and concentrated to dryness in vacuo. The
residue was chromatographed on a silicagel column eluting
with hexane and ethyl acetate (1:2) to give seco-acid 20
(91 mg, 66%) as an amorphous solid. Because NMR
spectrum of the seco-acid showed peak broadening, the
seco-acid was characterized as its methyl ester 21.
3.2.9. (9R)-3,5-O-Isopropylidene-8,8a-deoxa-9-dihydro-
oleandonilide (18). To a cooled (225 8C) solution of 17
200 mg, 0.49 mmol) in THF (7.5 ml) was added CeCl3.
7H2O (94 mg, 0.54 mmol) and after stirring for 1 h, NaBH4
30 mg, (0.79 mmol) was added to the suspension and the
mixture was stirred for 4.5 h at 225 8C and treated with sat.
NH4Cl and extracted with ether. The combined extract was
washed with brine and dried over Na2SO4 and evaporated to
dryness in vacuo. The residue was chromatographed on a
silicagel column eluting with hexane and ethyl acetate (3:1)
to afford diol 18 (205 mg, quantitative yield) as an
amorphous solid.
3.2.12. (9R)-3,5:9,11-Bis-O-isopropilidene-9-dihydro-
oleandonolide seco-acid methyl ester (21). To a solution
of 20 (10.0 mg, 21.3 mmol) in benzene 1.0 ml) was added
MeOH (200 ml) and 10% hexane solution of trimethyl-
silyldiazomethane (200 ml, 176 mmol) and the solution was
stirred for 45 min and then treated with acetic acid and the
1
[a]2D1¼25.08 (c¼1.20). H NMR (400 MHz, C6D6) d. 5.48
(1H, s), 5.46 (1H, dd, J¼6.6, 1.0 Hz), 5.07 (1H, s), 4.33 (1H,

T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
4701
solution was diluted with ether and washed with sat.
NaHCO3 and brine and dried over Na2SO4 and concentrated
to dryness in vacuo. The residue was chromatographed on a
silicagel column eluting with hexane and ethyl acetate (4:1)
to give methyl ester 21 (10.3 mg, quantitative) as an
amorphous solid.
broadening, the seco-acid was characterized as its methyl
ester 24.
[a]2D3¼251.48 (c¼1.00, CHCl3). IR (neat) 1710, 1640,
1610 cm21. MS (EI) m/z 560 (Mþ). HRMS (EI) m/z Calcd
for C33H52O7 (Mþ) 560.3713, found 560.3738.
[a]2D1¼220.08 (c¼0.78). 1H NMR (400 MHz, C6D6) d 5.08
(1H, br. s), 4.92 (1H, br. s), 4.13 (1H, br. s). 4.06 (1H, dd,
J¼2.0, 5.0 Hz), 4.02 (1H, dd, J¼4.4, 10.7 Hz), 3.87 (1H, d,
J¼7.3 Hz), 3.37 (3H, s), 3.35 (1H, dd, J¼2.0, 10.3 Hz), 3.09
(1H, br. d, J¼14.2 Hz), 2.87 (1H, m), 2.22–2.28 (1H, m),
2.05–2.15 (2H, m), 1.78–1.88 (2H, m), 1.64 (1H, dd,
J¼10.7, 13.7 Hz), 1.49 (3H, s), 1.43 (3H, s), 1.39 (3H, d,
J¼6.8 Hz), 1.36 (3h, S), 1.30, 3h, S), 1.15 (3H, d, J¼
6.4 Hz), 1.13 (3H, d, J¼7.3 Hz), 0.91 (3H, d, J¼6.8 Hz),
0.80 (3H, d, J¼6.4 Hz), 0.67 (3H, d, J¼7.3 Hz). MS (EI)
m/z 484 (Mþ). HRMS (EI) m/z Calcd for C27H48O7 (Mþ)
484.3400, found 484.3410.
3.2.15. (9R)-3,5-O-Isopropylidene-9,11-O-(2,4,6-tri-
methylbenzylidene)-8,8a-deoxa-9-dihydrooleandonolide
seco-acid methyl ester (24). A solution of 23 (20.0 mg,
35.7 mmol) and MeOH (400 ml) and 10% hexane solution of
Me3SiCHN2 (400 ml, 35.7 mmol) was stirred for 45 min at
room temperature and then treated with acetic acid and the
solution was diluted with ether and washed with sat.
NaHCO3 and brine and dried over Na2SO4 and concentrated
to dryness in vacuo. The residue was chromatographed on
a silicagel column eluting with hexane and ethyl acetate
(4:1) to give methyl ester 24 (18 mg, 88%) as an amorphous
solid.
3.2.13. 3,5-O-Isopropylidene-9,11-O-(2,4,6-trimethyl-
benzylidene)-(9R)-8,8a-deoxa-9-dihydrooleandonolide
(22). A solution of diol 18 (205 mg, 0.50 mmol) and
mesitaldehyde dimethylacetal (291 mg, 1.50 mmol) and
camphorsulfonic acid (3 mg) was stirred for 6 h at room
temperature. The solution was treated with sat. NaHCO3
and extracted with CH2Cl2 and the combined extract was
washed with sat. NaHCO3 and brine and dried over Na2SO4
and concentrated to dryness in vacuo. The residue was
chromatographed on a silicagel column eluting with hexane
and ethyl acetate to give 22 (180 mg, 66%) as an amorphous
solid.
[a]2D1¼249.38 (c¼0.67, CHCl3). EIMS m/z 574 EIHRMS
m/z 574.3852 (MþH)þ [Calcd for C34H54O7 (Mþ)
574.3870]. 1H NMR (400 MHz, C6C6) d 6.75 (2H, s),
6.23 (1H, s), 5.21 (1H, s), 5.17 (1H, s), 4.39 (1H, s), 4.25
(1H, dd, J¼2.0, 9.8 Hz), 4.01–4.06 (1H, m), 3.99 (1H, dd,
J¼1.5, 10.3 Hz), 3.36 (1H, s), 3.27 (1H, dd, J¼8.3, 1.5 Hz),
2.93 (1H, d, J¼14.2 Hz), 2.81 (1H, dq, J¼10.0, 6.8 Hz),
2.65 (6H, s), 2.11 (3H,s), 2.07 (1H, dd, J¼6.3, 12.7 Hz),
1.85–1.97 (2H, m), 1.69–1.75 (2H, m), 1.38–1.42 (1H, m),
1.35 (3H, d, J¼6.8 Hz), 1.31 (3H, s), 1.23 (3H, s), 1.02–
1.06 (6H, m), 0.78 (3H, d, J¼6.8 Hz), 0.71 (3H, d,
J¼6.8 Hz). 13C (100.4 MHz, C6D6) d 174.7, 146.5, 137.1,
130.1, 128.6, 127.9, 114.0, 99.3, 81.2, 78.4, 75.7, 67.8, 51.1,
42.5, 40.0, 38.2, 32.8, 32.0, 29.8, 29.2, 20.9, 19.9, 19.6,
15.4, 14.0, 13.8, 9.5, 5.4. MS (EI) m/z 574 (Mþ). HRMS
(EI) m/z Calcd for C33H52O7 (Mþ) 574.3870, found
574.3852.
[a]2D3¼239.28 (c¼0.31, CHCl3). IR (neat) 1720, 1630,
1610 cm21. 1H NMR (400 MHz, C6C6) d 6.82 (2H, s), 6.44
(1H, s), 5.86 (1H, dq, J¼7.0, 1.0 Hz), 5.74 (1H, br. s), 5.28
(1H, br. s), 4.48 (1H, dd, J¼2.0, 7.0 Hz), 4.37 (1H, br. s),
3.97 (1H, dd, 1.0, 10.7 Hz), 3.61 (1H, d, J¼1.0, 9.8 Hz),
2.88 (6H, s), 2.80–2.85 (1H, m), 2.57–2.63 (1H, m), 2.13
(3H, s), 1.93 (1H, dd, J¼6.8, 13.2 Hz), 1.80–1.87 (3H, m),
1.67 (1H, dd, J¼17.1, 2.5 Hz), 1.58 (3H, s), 1.52 (1H, m),
1.45 (3H, s), 1.39 (3H, d, J¼6.8 Hz), 1.36 (3H, d,
J¼6.3 Hz), 1.21 (3H, d, J¼6.8 Hz), 1.19 (3H, d,
J¼6.8 Hz), 0.90 (3H, d, J¼6.8 Hz), 0.73 (3H, J¼7.3 Hz).
13C NMR (100.4 MHz, C6D6) d 174.4, 143.1, 138.1, 137.7,
132.1, 130.2, 128.6, 127.9, 111.8, 100.5, 98.0, 82.4, 78.1,
72.3, 69.3, 41.9, 70.3, 34.1, 32.6, 30.1, 29.5, 20.9, 19.6,
18.2, 16.4, 13.7, 13.1, 7.98, 7.14. MS (EI) m/z 542 (Mþ).
HRMS (EI) m/z Calcd for C33H50O6 (Mþ) 542.3608542,
found 542.3608.
3.2.16. (9R)-9-Dihydro-3,5-O-(2,4,6-trimethylbenzyl-
idene)-oleandonolide (25). To a cooled (0 8C) solution of
10 in iso-propanol and ethyl acetate (1:2, 48 ml) was added
sodium borohydride (60.4 mg, 1.60 mmol), and the solution
was stirred for 15 min at room temperature, and treated with
sat. NH4Cl and extracted with CH2Cl2 and the combined
extract was washed with brine and dried over Na2SO4 and
concentrated to dryness in vacuo. The residue was
chromatographed on a silicagel column eluting with hexane
and ethyl acetate (2:1) to give 25 (399 mg, 97%) as an
amorphous solid.
[a]2D1¼26.47 (c¼0.66, CDCl3). IR (neat) 1735, 1620 cm21
.
3.2.14. (9R)-3,5-O-Isopropylidene-9,11-O-(2,4,6-tri-
methylbenzylidene)-8,8a-deoxa-9-dihydrooleandonolide
seco-acid (23). A solution of the 22 160 mg, 0.30 mmol)
and 5 N-NaOH (1.7 ml, 8.5 mmol) was stirred for 12 h at
90 8C, and after cooling to rt, was extracted with ether. The
aqueous layer was neutralized with 10% HCl and extracted
with ether. The combined extract was washed with water
and brine and dried over Na2SO4 and concentrated to
dryness in vacuo. The residue was chromatographed on a
silicagel column eluting with hexane and ethyl acetate to
give seco-acid 23 163 mg, 97%) as an amorphous solid.
Because NMR spectrum of the seco-acid 23 showed peak
1H NMR (270 MHz, C6D6) d 6.78 (2h, S), 6.08 (1h, s), 5.70
(1H, dq, J¼0.8, 6.8 Hz), 4.21 (1H, dd, J¼1.1, 7.3 Hz), 4.10
(1H, m), 4.03 (1H, dd, J¼1.5, 10.8 Hz), 3.75 (1H, d,
J¼10.2 Hz), 3.54 (1H, dd, J¼3.5, 10.2 Hz), 3.22 (1H, d,
J¼5.8 Hz), 3.14 (1H, d, J¼5.3 Hz), 2.90 (1H, dq, J¼6.6,
10.8 Hz), 2.57 (6H, s), 2.32 (1H, d, J¼5.3 Hz), 2.21 (1H,
m), 2.13 (3H,s), 1.94–2.09 (2H, m), 1.84 (1H, m), 1.66 (1H,
dd, J¼12.5, 15.6 Hz), 1.37 (3H, d, J¼6.6 Hz), 1.36 (3H, d,
J¼6.8 Hz), 1.17 (3H, d, J¼6.7 Hz), 1.11 (3H, d, J¼6.8 Hz),
1.02 (3H, d, J¼6.8 Hz), 0.74 (3H, d, J¼7.0 Hz). MS (EI)
m/z 518 (Mþ). HRMS (EI) Calcd for C30H46O7 (Mþ)
518.3241, found 518.3291.

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T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
3.2.17. (9R)-9-Dihydro-3,5:9,11-bis-O-(2,4,6-trimethyl-
benzylidene)-oleandonolide (26). solution of 25
temperature. The mixture was diluted with CH2Cl2 and
washed with sat. NaHCO3 and sat. NH4Cl and brine
consecutively, and the aqueous layer was extracted with
CH2Cl2. The combined organic layer was dried on MgSO4
and the residue was concentrated to dryness in vacuo. The
residue was chromatographed on a silicagel column eluting
with hexane and ethyl acetate (10:1) to give 28 (160 mg,
74%) as an amorphous solid.
A
(250 mg, 482 mmol) and mesitaldehyde dimethylacetal
(118 mg, 965 mmol) and camphorsulfonic acid (10 mg,
43 mmol) in CH2Cl2 (5 ml) was stirred for 5 h at room
temperature, and then treated with excess triethylamine.
The reaction mixture was concentrated in vacuo and the
residue was chromatographed on a silicagel column
eluting with hexane and ethyl acetate (15:1 to 1:1) to give
26 (188 mg, 90% based on reacted 25) as an amorphous
solid and recovered 25 (75.5 mg, 33%) as an amorphous
solid.
1H NMR (400 MHz, C6D6) d 6.96 (1H, s), 6.73 (2H, s), 6.71
(2H, s), 5.87 (1H, s), 4.65 (1H, dd, J¼2.5, 10.3 Hz), 3.94
(1H, m), 3.85 (1H, s), 3.64 (1H, dd, J¼2.1, 9.4 Hz), 3.37
(1H, dd, J¼4.3, 10.2 Hz), 3.54 (1H, dd, J¼4.3, 10.2 Hz),
3.31 (1H, s), 3.22 (1H, dd, J¼2.1, 9.7 Hz), 2.89 (1H, d,
J¼9.8 Hz), 2.69 (6H, s), 2.16 (1H, m), 2.12 (3H, s), 2.11
(3H, s), 2.08 (1H, m), 1.72–1.92 (3H, m), 1.40 (3H, s), 1.40
(3H, d, J¼7.0 Hz), 1.14 (3H, d, J¼6.8 Hz), 1.14 (3H, d,
J¼6.8 Hz), 1.12 (3H, d, J¼7.2 Hz), 1.02 (9H, s), 0.80 (3H,
d, J¼7.0 Hz), 0.34 (3H, d, J¼7.1 Hz), 0.08 (3H, s), 0.07
(3H, s). MS (EI) m/z 768 (Mþ). HRMS (EI) m/z Calcd for
C46H76O7Si (Mþ) 768.5360, found 768.5412.
[a]D23¼275.8 (c¼0.63, CDCl3).IR (neat) 1730 cm21
.
1H
NMR (400 MHz, C6D6) d 7.17 (1H, s), 6.78 (2H, s), 6.77
(2H, s), 6.10 (1H, s), 5.88 (1H, dq, J¼0.7, 6.7 Hz), 4.61 (1H,
dd, J¼0.8, 5.2 Hz),4.22 (1H, dd, J¼1.1, 10.8 Hz), 4.01 (1H,
dd, J¼1.1, 9.3 Hz), 3.78 (1H, s), 2.94 (1H, dq, J¼6.8,
10.8 Hz), 2.91 (6H, s), 2.72 (1H, d, J¼5.4 Hz), 2.53 (6H, s),
2.20 (1H, m), 2.18 (1H, d, J¼5.4 Hz), 2.12 (3H, s), 2.10
(3H, s), 2.05 (1H, m), 1.90–2.00 (2H, m), 1.57 (1H,), 1.44
(3H, d, J¼6.8 Hz), 1.41 (3H, d, J¼6.8 Hz), 1.38 (3H, d,
J¼6.8 Hz), 1.13 (3H, d, J¼6.4 Hz), 0.94 (3H, d, J¼6.7 Hz),
0.88 (3H, d, J¼7.3 Hz). MS (EI) m/z 648 (Mþ). HRMS
(EI) m/z Calcd for C40H56O7 (Mþ) 648.4023, found
648.4030.
3.2.20. (2R,3R,4S,5R,6R,7S,9R,10R,11S,12R,13S)-2-Acet-
oxy-14-[(t-butyl)dimethylsilyloxy]-3,5,7,9,11,13-hexa-
methyl-4,6:10,12-bis-(2,4,6-trimethylbenzylidenedioxy)-
tetradecane-7-ol (29).
A solution of 28 (137 mg,
178 mmol) and triethylamine (81 ml, 582 mmol) and acetic
anhydride (22 ml, 235 mmol) and DMAP (5 mg, 41 mmol)
in CH2Cl2 was stirred for 33 h at room temperature. The
solution was washed with sat. NaHCO3, and sat NH4Cl, and
the combined aqueous layer was extracted with CH2Cl2.
The combined organic layer was dried on MgSO4 and
concentrated to dryness in vacuo. The residue was
chromatographed on a silicagel column eluting with hexane
and ethyl acetate (10:1) to give 29 (137 mg, 95%) as an
amorphous solid.
3.2.18. (2S,3R,4S,5R,6R,8S,10R,11S,12R,13R)-2,4,6,
8,10,12-Hexamethyl-3,5:9,11-bis-(2,4,6-trimethylbenzyl-
idenedioxy)-tetradecane-1,8,13-triol (27). To a solution of
lactone 26 (343 mg, 529 mmol) in ether (10 ml) was added
LiAlH4 (60.2 mg, 1.59 mmol) in ether (1 ml), the reaction
mixture was stirred for 2 h at 30 8C. To the mixture was
added water (60 ml) and 15% NaOH (60 ml) and water
(180 ml) consecutively. The reaction mixture was stirred for
1 h, and dried over Na2SO4. After stirring over night, an
insoluble material was filtered thru a pad of celite and
washed with ether. The combined filtrate was concentrated
to dryness and the residue was chromatographed on a
silicagel column eluting with hexane and ethyl acetate (1:1)
to give 27 (294 mg, 85%).
[a]D21¼223.2 (c¼1.06, CDCl3).IR (neat) 1740 cm21
.
1H
NMR (270 MHz, C6D6) d 6.80 (2H, s), 6.75 (1H, s), 6.72
(2H, s), 5.89 (1H, s), 5.59 (1H, dq, J¼1.7, 6.8 Hz), 4.34 (1H,
dd, J¼2.2, 10.8 Hz), 3.65 (1H, dd, J¼1.5, 9.2 Hz), 3.55 (1H,
dd, J¼4.1, 10.3 Hz), 3.43 (1H, s), 3.38 (1H, dd, J¼4.1,
10.3 Hz),3.37 (1H, s), 3.25 (1H, dd, J¼1.5, 10.4 Hz), 2.79
(6H, s), 2.52 (6H, s), 2.17 (1H, m), 2.12 (6H, s), 1.85 (3H, s),
1.78–1.94 (3H, m), 1.62 (1H, m), 1.42 (3H, s), 1.36 (3H, d,
J¼7.1 Hz), 1.16 (3H, d, J¼6.7 Hz), 1.15 (3H, d,
J¼6.78 Hz), 1.03 1.02 (3H, d, J¼7.0 Hz), 0.81 (3H, d,
J¼6.9 Hz), 0.44 (3H, s), 0.43 (1H, d, J¼6.8 Hz), 0.08 (3H,
s), 0.07 (3H, s). MS (FAB) m/z 811 (Mþþ1). HRMS (FAB)
m/z Calcd for C48H79O8Si (Mþþ1) 811.5540, found
811.5545.
1H NMR (400 MHz, C6D6) d 6.95 (1H, s), 6.73 (2H, s), 6.71
(2H, s), 5.79 (1H, s), 4.64 (1H, dd, J¼2.8, 10.8 Hz), 3.94
(1H, m), 3.82 (1H, s), 3.52 (1H, dd, J¼2.0, 9.3 Hz), 3.31
(1H, s), 3.26 (1H, dd, J¼4.8, 11.0 Hz), 3.20 (1H, dd, J¼4.8,
11.0 Hz), 3.09 (1H, dd, J¼2.1, 10.1 Hz), 2.78 (1H, d,
J¼9.5 Hz), 2.51 (6H, s), 2.15 (1H, m), 2.12 (3H, s), 2.06
(1H, m), 1.85 (1H, ddd, J¼2.9, 6.9, 10.8 Hz), 1.66–1.79
(2H, m), 1.46 (1H, dd, J¼10.8, 13.5 Hz), 1.38 (3H, s), 1.38
(3H, d, J¼6.9 Hz), 1.11 (3H, d, J¼6.6 Hz), 1.06 (3H, d,
J¼6.7 Hz), 1.03 (3H, d, J¼6.7 Hz), 0.73 (3H, d, J¼7.0 Hz),
0.39 (3H, d, J¼7.2 Hz). MS (EI) m/z 653 (Mþ21)). HRMS
(EI) m/z Calcd for C40H61O7 653. (Mþ21) 4414, found
653.4408.
3.2.21. (2S,3R,4S,5R,6R,8S,9R,10R,11S,12R,13R)-13-
Acetoxy-2,4,6,8,10,12-hexamethyl-3,5:9,11-bis-(2,4,6-tri-
methylbenzylidenedioxy)-tetradecane-1,8-diol (30). To a
solution of 29 (131 mg, 161 mmol) in THF (5 ml) was added
1 M THF solution of TBAF (320 ml, 320 mmol), and the
solution was stirred for 3.5 h at room temperature and
treated with brine and extracted with CH2Cl2. The extract
was dried on MgSO4 and concentrated to dryness in vacuo.
The residue was chromatographed on a silicagel eluting
with hexane and ethyl acetate (2:1) to give 30 (111 mg,
99%) as an amorphous solid.
3.2.19. (2R,3R,4S,5R,6R,7S,9R,10R,11S,12R,13S)-14-[(t-
Butyl)dimetylsilyloxy]-3,5,7,9,11,13-hexamethyl-
4,6:10,12-bis-(2,4,6-trimethylbenzylidenedioxy)-tetra-
decane-2,7-diol (28). A solution of 27 (185 mg, 238 mmol)
and triethylamine (66.3 ml, 476 mmol) and t-butyldimethyl-
silyl chloride (59.8 mg, 397 mmol) and DMAP (4 mg,
32.7 mmol) in CH2Cl2 (5 ml) was stirred for 32 h at room

T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
4703
1
[a]2D1¼218.8 (c¼1.22, CDCl3). IR (neat) 1740 cm21. H
NMR d 6.68 (2H, s), 6.74 (1H, s), 6.71 (2H, s), 5.81 (1H, s),
5.59 (1H, dq, J¼2.3, 6.7 Hz), 4.34 (1H, dd, J¼2.6, 10.3 Hz),
3.52 (1H, dd, J¼1.9, 9.8 Hz), 3.43 (1H, s), 3.28 (1H, s), 3.25
(1H, dd, J¼4.7, 10.4 Hz), 3.18 (1H, dd, J¼4.7, 10.4 Hz),
3.10 (1H, dd, J¼1.8, 9.7 Hz), 2.78 (6H, s), 2.52 (6H, s), 2.12
(6H, s), 2.11 (1H, m), 1.91 (1H, dq, J¼2.1, 7.0 Hz) 1.85
(3H, s), 1.40 (3H, s), 1.34 (3H, d, J¼7.0 Hz), 1.08 (3H, d,
J¼6.8 Hz), 1.05 (3H, d, J¼6.7 Hz), 1.03 (3H, d, J¼6.8 Hz),
0.72 (3H, d, J¼7.1 Hz), 0.45 (3H, d, J¼7.0 Hz). MS (EI)
m/z 696 (Mþ). HRMS (EI) m/z Calcd for C42H64O8 (Mþ)
696.4601, found 696.4622.
3.2.24. (8S,9R)-3,5-O-Isopropylidene-9,11-O-(2,4,6-tri-
meethylbenzylidene)-8-hydroxy-8,8a-d4eoxa-9-dihydro-
oleandonolide seco-acid methyl ester (33). To a solution
of 32 (17 mg, 25.4 mmol) in benzene (1.0 ml) was added
MeOH (200 ml) and 10% hexane solution of trimethyl-
silyldiazomethane (200 ml, 176 mmol) and the solution was
stirred for 1 h and then treated with acetic acid and the
solution was diluted with ether and washed with sat.
NaHCO3 and brine and dried over Na2SO4 and concentrated
to dryness in vacuo. The residue was chromatographed on a
silicagel column eluting with hexane and ethyl acetate (4:1)
to give methyl ester 33 (15.6 mg, 90%) as an amorphous solid.
1
3.2.22. (8S,9R)-13-O-Acetyl-3,5-O-isopropylidene-9,11-
O-(2,4,6-trimeethylbenzylidene)-8-hydroxy-8,8a-deoxa-
9-dihydro-oleandonolide seco-acid (31). To a cooled
(240 8C) solution of 30 (102 mg, 146 mmol) in acetone
(3.5 ml) was added 2.67 M Jones reagent (106 ml.
283 mmol) and the solution was stirred for 5 h at 230 8C,
then treated with isopropanol and diluted with water, and
extracted with CH2Cl2. The combined extract was dried on
MgSO4 and concentrated to dryness in vacuo. The residue
was chromatographed on a silicagel column eluting with
hexane and ethyl acetate (1:2) to give 31 (83 mg, 80%) as an
amorphous solid.
[a]1D9¼216.9 (c¼0.76, CDCl3). IR (neat) 1720 cm21. H
NMR (500 MHz, C6D6) 6.95 (1H, s), 6.73 (2H, s), 6.70 (2H,
s), 5.76 (1H, s), 4.69 (1H, dd, J¼10.6, 2.4 Hz), 3.98 (1H, dd,
J¼10.1, 6.8 Hz), 3.95 (1H, broad s), 3.69 (1H, s), 3.36 (3H,
s), 3.09 (1H, dd, J¼10.2, 6.8 Hz), 2.86 (1H, dq, J¼6.8,
10.1 Hz), 2.67 (6H, s), 2.48 (6H, s), 2.12 (3H, s), 2.11 (3H,
s), 2.10 (1H, m), 1.86 (1H, m), 1.69 (1H, dd, J¼14.4,
5.4 Hz), 1.38 (3H, d, J¼7.2 Hz), 1.34 (3H, s), 1.29 (3H, d,
J¼6.8 Hz), 1.13 (3H, d, J¼6.9 Hz), 1.11 (3H, d, J¼6.6 Hz),
1.00 (1H, dd, J¼14.0, 2.7 Hz), 0.66 (3H, d, J¼7.1 Hz), 0.37
(3H, d, J¼7.1 Hz). 13C NMR (125 MHz, C6D6) 174.29,
139.61, 137.57, 136.92, 132.75, 130.80, 130.34, 13o.12,
128.26, 127.44, 102.63, 96.78, 87.67, 86.30, 83.56, 78.70,
79.64, 70.46, 59.97, 51.20, 46.18, 42.64, 39.77, 32.10,
39.14, 29.47, 28.49, 24.16, 20.85, 20.79, 20.60, 18.70,
18.08, 15.30, 15.15, 14.14, 10.93, 6.71. MS (FAB) m/e 683
(Mþþ1). EXMS (FAB) m/z Calcd for C41H63O8 683.4544
(Mþþ1), found 683.4555.
IR (neat) 1745 cm21. 1H NMR d 6.81 (2H, s), 6.72 (3H, s),
5.79 (1H, s), 5.59 (1H, dq, J¼2.2, 6.6 Hz), 4.31 (1H, dd,
J¼2.5, 10.7 Hz), 3.86 (1H, dd, J¼2.1, 9.8 Hz), 3.39 (1H, s),
3.09 (1H, dd, J¼1.8, 9.7 Hz), 2.86 (1H, dq, J¼6.7, 10.6 Hz),
2.78 (6H, s), 2.48 (6H, s), 2.13 (6H, s), 2.02–2.18 (2H, m),
1.83–1.90 (1H, m), 1.87 (3H, s), 1.56–1.79 (2H, m), 1.37
3H, s), 1.34 (3H, d, J¼7.1 Hz), 1.29 (3H, d, J¼7.0 Hz), 1.17
(3H, d, J¼6.8 Hz), 1.03 (3H, d, J¼6.6 Hz), 0.67 (3H, d,
J¼7.1 Hz), 0.45 (3H, d, J¼7.1 Hz). MS (EI) m/z 710 (Mþ).
HRMS (EI) m/z Calcd for C42H62O9 (Mþ) 710.4394, found
710.4432.
3.3. General methods of lactonization of seco-acid 14, 20,
23 and 32
3.3.1. Lactonization under the high dilution condition.
To a solution of seco-acid (1, 20, 33) (0.047 mmol) in THF
(0.95 ml) was added triethylamine (7.2 ml, 52 mmol) and
2,4,6-trichlorobenzoyl chlodide (7.4 ml, 0.047 mmol) and
the solution was stirred for 19.5 h and then diluted with
toluene (24 ml) and transferred to a syringe. The solution in
the syringe was added to a solution of DMAP (139 mg,
1.18 mol) in toluene (20 ml) at 130 8C over 5 h with micro
feeder syringe pump. The resulting mixture was stirred for
further 6 h at 130 8C. After cooling to rt, the mixture was
concentrated to dryness in vacuo and the residue was treated
with sat. NH4Cl and extracted with ether and the combined
extract was washed with brine and dried over Na2SO4 and
concentrated to dryness in vacuo. The residue was
chromatographed on a silicagel column eluting with hexane
and ethyl acetate (10:1) to give lactone 13 (97%) from14, 19
(15%) from 20, 22 (96%) from 23, and 34 (0%) from 32.
3.2.23. (8S,9R)-3,5-O-Isopropylidene-9,11-O-(2,4,6-tri-
meethylbenzylidene)-8-hydroxy-8,8a-deoxa-9-dihydro-
oleandonolide seco-acid (32). To a solution of 31 (55 mg,
77.5 mmol) in MeOH (3 ml) was added 15% NaOH
(0.6 ml, 2.25 mol). The reaction mixture was stirred for
24 h and then treated with phosphate buffer (pH7),
extracted with ether and the extract was washed with
brine and dried over MgSO4 and concentrated to dryness
in vacuo. The residue was chromatographed on a silicagel
column eluting with MeOH and CH2C2 (1:50) to give
seco-acid 32 (48 mg, 93%) as an amorphous solid.
Because this seco-acid could not be purified completely,
analytical data was taken after conversion to its methyl
ester 33.
1
IR (neat) 1735 cm21. H NMR (400 MHz, C6D6) d 6.92
3.3.2. Lactonization under the normal condition. To a
solution of seco-acid (35.7 mmol) in THF (3.5 ml) was
added triethylamine (5.5 ml, 40 mmol) and 2,4,6-trichloro-
benzoyl chloride (5.6 ml, 36 mmol) at room temperature and
the solution was stirred for 17 h and then to the mixture was
added DMAP (13.2 mg, 108 mmol), and after stirring for
further 3 h the mixture was concentrated to dryness in vacuo
and the residue was treated with sat. NH4Cl and extracted
with ether. The combined extract was washed with brine and
dried over Na2SO4 and concentrated to dryness in vacuo.
(1H, s), 6.74 (2H, s), 6.71 (2H, s), 5.76 (1H, s), 4.62 (1H, dd,
J¼2.5, 9.7 Hz), 3.96 (1H, dq, J¼2.4, 6.6 Hz), 3.83 (1H, dd,
J¼1.8, 10.2 Hz), 3.29 (1H, s), 3.07 (1H, dd, J¼1.8,
10.5 Hz), 2.81 (1H, dq, J¼7.0, 10.3 Hz), 2.66 (6H, s),
2.46 (6H, s), 2.12 (3H, s), 2.11 (3H, s), 2.01–2.13 (2H, m),
1.89 (1H, m), 1.82 (1H, dq, J¼2.5, 7.0 Hz), 1.34 (3H, d,
J¼7.1 Hz), 1.28 (3H, d, J¼6.9 Hz), 1.13 (3H, d, J¼6.9 Hz),
1.11 (3H, d, J¼6.6 Hz), 0.67 (3H, d, J¼6.8 Hz), 0.35 (3H, d,
J¼7.0 Hz). MS (EI) m/e 668 (Mþ).

4704
T. Hamada et al. / Tetrahedron 60 (2004) 4693–4704
The residue was chromatographed on a silicagel column
eluting with hexane and ethyl acetate (10:1) to give lactone
13 (82%), 19 (0%), and 22 (81%).
conformers have a conformational distance dAB shorter than
108, they belong to the same cluster.
3.3.3. The attempted lactonization of seco-acid 32 (34).
To a solution of seco-acid 33 (15.4 mg, 23 mmol) in THF
(0.5 ml) was added triethylamine (5.2 ml, 34.5 mmol), and
2,4,6-trichlorobenzoyl chloride (5.4 ml, 11.5 mmol), and
then the solution was stirred for 20 h at rt, and diluted with
toluene (10 ml). The solution was transferred to syringe,
added over 8.5 h with a syringe pump to a refluxed solution
of DMAP (65 mg, 530 mmol) in toluene (20 ml), the
mixture was stirred for 11.5 h under reflux. The mixture
was cooled to rt, and concentrated to dryness in vacuo. The
residue was treated with sat. NH4Cl and extracted with
ether. The combined extract was washed with brine, dried
over MgSO4. The residue was chromatographed on a
silicagel column eluting with hexane and ethyl acetate (10:1
to 1:1) to give complicated product and the desired lactone
33 (0%) (Scheme 4).
References and notes
1. For preliminary communication, see: Hamada, T.; Kobayashi,
Y.; Kiyokawa, M.; Yonemitsu, O. Tetrahedron Lett. 2003, 44,
4343.
2. Gaumann, E.; Hutter, R.; Keller-Schierlein, W.; Neipp, L.;
Prelog, V.; Zahner, H. Helv. Chim. Acta 1960, 43, 601.
3. Muntwyler, R.; Keller-Schierlein, W. Helv. Chim. Acta 1972,
55, 460.
4. Fragment synthesis: (a) Kotchetkov, N. K.; Yashunsky, D. V.;
Sviridov, A. F.; Ermenko, M. S. Carbohydr. Res. 1990, 200,
209. (b) Raimundo, B. C.; Heathcock, C. H. Synlett 1995,
1213. (c) Paterson, I. Tetrahdron Lett. 1983, 24, 1311. seco-
Acid synthesis: (d) Raimundo, B. C. The total synthesis of the
lankanolide seco-acid, dissertation; University of California:
Berkeley, CA, USA, 1996.
3.4. Conformation calculations of model seco-acids (4, 6
and 8) and corresponding lactones (3, 5, 7), and
clustering of conformers
5. For example, (a) Stork, G.; Paterson, I.; Lee, F. K. C. J. Am.
Chem. Soc. 1982, 104, 4686. (b) Stork, G.; Rychnovsky, S. D.
J. Am. Chem. Soc. 1987, 109, 1565. (c) Woodward, R. B.; et al.
J. Am. Chem. Soc. 1981, 103, 3213.
Conformation calculation of model seco-acids and the
corresponding lactones were carried out by a confor-
mational space searching algorism ‘CONFLEX ver.4’
working on PC-unix (Linux). Extended MM2 was used as
the energy minimizer. The conformers obtained by
conformation search were classified into clusters using the
single lincage algorithm accelelated by the doubly linked
list method.8a,b The conformational similarity between a
pair of conformers (clusters) A and B was measured by
conformational distance, dAB, defined as the root-mean-
square difference in the major backbone and ring dihedral
angles (Eq. 1):8c
6. For a previous report related to conformation analysis for
synthetic design; see (a) Hamada, T. Prediction of macro-
lactonization results-conformation calculation of macrolide
seco-acid derivatives computer aided innovation of new
materials II. Part 1; 1993; p. 829. (b) Makino, K.; Nakajima,
N.; Hashimoto, N.; Yonemitsu, O. Tetrahedron Lett. 1996, 37,
9077. and references cited therein.
7. Goto, H.; Osawa, E. J. Chem. Soc., Perkin Trans. 2 1993, 187.
We used the latest version 4.02 of conflex working on pc-unix
(linux) and using extended MM2 as a force field.
8. (a) Osawa, E.; Goto, H.; Hata, T.; Deretey, E. J. Mol. Struct.
(Theochem.) 1997, 398-399, 229. (b) For classification in to
clusters, see Kunuth, D. K. The art of computer programming;
Addison-wiley: Menlo Park, CA, 1973; Vol. 1. p 279. (c) For
the definition of cluster distance, see Saunders, M. J. Comput.
Chem. 1991, 12, 645.
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u
17
X
u
u
u
t
ðwAi 2 wBi Þ2
i¼1
dAB
¼
ð1Þ
17
where wAi and wBi are the i-th dihedral angle of conformers A
and B, respectively. Seventeen dihedral angle used in Eq. 1
refer to nine backbone bonds along the segment of C3–C4–
C5–C6–C7–C8–C9–C10–C11–C12, and to four each
along the two dioxane rings, C3–O3–C (acetal or ketal
carbon)–O5–C5 and C9–O9–C (acetal or ketal carbon)–
O11–C11. The end portions, C3–C2–C1–OMe and C12–
C13–OH and OH and phenyl group rotation, was not
included in the cluster analysis, although all these bonds
were rotated during the conformation search. When a pair of
9. Conformations of the 6-membered acetal and ketal of syn-1,3-
diol (C3,C5) of seco-acids 4, 6 and 8 were shown to be fixed to
chair conformation.10 The substituents (methyl, phenyl or
dimethl group) on the 6-membered ring of the syn-1,3-diol are
far from the backbone chain, we can conclude that the
difference in the substituents does not affect the backbone
conformation.
10. Clode, D. M. Chem. Rev. 1979, 79, 491.
11. Paterson, I.; Arya, P. Tetrahedron 1988, 44, 253.
12. Hamada, T.; Kobayashi, Y. Tetrahedron Lett. 2003, 44, 4347.