The first stereoselective total synthesis of lankanolide. Part 1: Computer-assisted design and lactonization of model seco-acid derivatives

Article abstract of DOI:10.1016/S0040-4039(03)00954-7

To design easily cyclizable seco-acid derivatives of lankanolide, the conformation of several model seco-acids was calculated and the lactonization experiments of the seco-acids were carried out to elucidate the efficiency of the cyclization of the model

Full text of DOI:10.1016/S0040-4039(03)00954-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4343–4346
The first stereoselective total synthesis of lankanolide. Part 1:
Computer-assisted design and lactonization of model seco-acid
derivatives
Tatsuo Hamada,* Yukinari Kobayashi, Mitsugu Kiyokawa and Osamu Yonemitsu†
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 6 March 2003; revised 7 April 2003; accepted 11 April 2003
Abstract—To design easily cyclizable seco-acid derivatives of lankanolide, the conformation of several model seco-acids was
calculated and the lactonization experiments of the seco-acids were carried out to elucidate the efficiency of the cyclization of the
model seco-acid. © 2003 Published by Elsevier Science Ltd.
The target molecule, lankanolide 2 is the aglicone of
(route b). Route a is via seco-acid II which has a
14-membered macrolide lankamycin 1. Lankamycin
tertiary alcohol at the C8 position. In route b, macro-
lactone IV is oxidized to prepare a tertiary alcohol at
the C8 after cyclization. The critical point of these two
routes will be the reactivity of seco-acids II and V. To
was isolated in 1960 by Gaumann et al.,1 and the
relative stereo-structure of the macrolide was deter-
mined in 1972 by Keller-Schlierlein et al. (Fig. 1,
Scheme 1).2 Since then, no report of the total synthesis
predict the reactivity of seco-acids II and V, first, we
of this macrolide has appeared, while synthetic efforts
calculate the conformation of the methyl ester of model
have been carried out.3 We are interested in the effect
seco-acid derivatives (4, 6 and 8) corresponding to
of the structure of the seco-acid derivative on the
seco-acids II and V, and the lactones (3, 5, and 7) (Fig.
efficiency of macrolactonization. In some cases, seco-
2).
acid derivatives did not cyclize to give macrolactone
derivatives. To avoid such a case, we decided to design
Recently Goto et al. developed a conformational search
the target seco-acid derivatives by computer-aided sim-
ulation before starting the synthesis.4 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
method of chain compounds by stepwise bond rotation
(conflex).5 First, we generated the three-dimensional
structures by using ‘conflex’ and the obtained conform-
ers were classified to conformation clusters.6 As shown
in Figure 3, the simulated conformation of the methyl
ester of the seco-acid 4 showed a conformation cluster
(15.2%) of the seco-acid has a similar conformation to
the corresponding cluster of lactone 3 (conformation
distance=8.7).7,8 On the other hand, the calculated
conformation of diacetonide seco-acid 6 showed no
similar conformation to the corresponding lactone 5
(conformation distance=48.1).8 The simulated confor-
mation of 8 methyl ester also did not contain a similar
conformation to the corresponding lactone 7 (confor-
mation distance=49.7).8 This result suggests that the
seco-acid 4 having a similar conformation to the corre-
sponding lactone will easily cyclize to form macrolac-
tone.8 The seco-acid having a tertiary alcohol at C8 (8)
and diacetonide seco-acid 6 were predicted not to
cyclize easily.
Figure 1. Lankamysin and lankanolide. Lankamysin (1):
R1=D-chalcose, R2=acetylarcanose. Lankanolide (2): R1=
H, R2=H.
* Corresponding author. E-mail: hamada@pharm.hokudai.ac.jp
† Present address: Department of Chemistry, Okayama University of
Science, Okayama 700-0005, Japan.
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00954-7

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T. Hamada et al. / Tetrahedron Letters 44 (2003) 4343–4346
Scheme 1. Retro synthetic analysis of lankanolide.
(12, 14 and 18) were prepared starting from the known
intermediate 9 reported by Paterson et al.,9 as shown in
Schemes 2 and 3. The iodide 9 was converted to
epoxy-acetonide 10 via deoxygenation to form exo-
olefin, following 1,2-reduction of enone to give diol 11
as a single diastereomer. The seco-acid 12 and 14 were
synthesized by a similar method. The diol of 11 was
acetalized with mesitaldehyde dimethylacetal and
hydolyzed with NaOH to form seco-acid 12. Similar
treatment of 11 with 2-methoxypropene, and NaOH
gave seco-acid 14. The seco-acid 18 was also synthe-
sized starting from 9, as shown in Scheme 3. Diol of 9
was protected as a mesitilidene acetal, following reduc-
tion of ketone, and the resulting diol was again pro-
tected as a mesitilidene acetal to give 16. The lactone
and epoxide were reduced with LAH to form a triol,
and the primary alcohol of the triol was protected as a
Figure 2. Model seco-acids and lactones for conformation
calculation.
To test the predicted reactivity of these three types of
seco-acids, we synthesized several model seco-acids,
and performed cyclization experiments. The seco-acids
Figure 3. Conformational distance between the cluster of lactone (3, 5 and 7) and the corresponding seco-acid (4, 6 and 8).

T. Hamada et al. / Tetrahedron Letters 44 (2003) 4343–4346
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Scheme 2. Preparation of model seco-acid derivatives 12 and 14. Reagents and conditions: (a) Me2C(OMe)2, PPTS, CH2Cl2, rt, 1
h; (b) aq-NaHCO3, THF, rt, 20 min; (c) CrCl2, acetone–H2O (2:1), rt, 30 min; (d) NaBH4, CeCl3, THF, −25°C, 4.5 h; (e)
MesCH(OMe)2, CSA, CH2Cl2, rt, 6 h; (f) 5N NaOH, DMSO, 90°C, 12 h; (g) 2-methoxypropene, PPTS, CH2Cl2, rt, 45 min; (h)
5N NaOH, DMSO, 90°C, 12 h.
Scheme 3. Preparation of seco-acid derivative 18. Reagents and conditions: (a) MesCH(OMe)2, CSA, CH2Cl2, rt, 30 min. (b)
NaBH4, i-PrOH–AcOEt (2:1), rt, 20 min. (c) MesCH(OMe)2, CSA, CH2Cl2, rt, 5 h. (d) LiAlH4, Et2O, 30°C, 2 h. (e) TBDMSCl,
Et3N, DMAP, CH2Cl2, rt, 24 h. (f) Ac2O, Et3N, DMAP, CH2Cl2, rt, 33 h. (g) n-Bu4NF, THF, rt, 3.5 h. (h) Jones reagent,
acetone, −30°C, 5 h. (i) 15% NaOH, MeOH, rt, 24 h.
Table 1. Cyclization reactions of several seco-acids
seco-Acid (mM)
Cyclization methoda
DMAP (mol equiv.)
Reaction temp.
Reaction time (h)
Yield (%)
12 (1.0)
12 (1.0)
14 (1.0)
14 (1.0)
18 (1.0)
A
B
A
B
A
2.5
3
2.5
2.5
2.5
130
Rt
130
Rt
11
3
43
43
43
96
81
15
0
130
0
a A: high-dilution condition: To a 6 mM toluene solution of DMPA in toluene, was added slowly a 2 mM toluene solution of the mixed anhydride
prepared from seco-acid and 2,4,6-trichlorobenzoyl chloride. B: normal condition: DMAP was added to a 10mM toluene solution of the mixed
anhydride.
TBDMS ether, and the secondary alcohol was acetyl-
ated to give 17. Deprotection of TBDMS and Jones
oxidation followed by deacetylation gave seco-acid 18.
The seco-acids (12, 14 and 18) were subjected to
macrolactonization.
give 19 at all even under the high dilution condition
(Table 1 and Scheme 4). The compatibility between
computer-simulated reactivity and chemical reactivity
is so important that the computer-simulated conforma-
tion analysis may predict the reactivity of intramolecu-
lar cyclization, and the most preferable model
seco-acid to synthesize lankanolide is the seco-acid 12.
In some cases, computer-assisted conformation analysis
can complement synthetic design. We are continuing
research along this line, and in the following report, we
describe a successful example of total synthesis of
lankanolide via the seco-acid designed according to the
model seco-acid 12.
The results of cyclization experiments are shown in
Table 1 and Scheme 4. As we predicted, seco-acid 12
cyclized smoothly to give macrolactone 13 in high
yield, even under the normal concentration conditions.
On the other hand, seco-acid 14 (diacetonide) cyclized
sluggishly to form lactone 15 in low yield even under
the high dilution condition. The seco-acid 18 did not

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T. Hamada et al. / Tetrahedron Letters 44 (2003) 4343–4346
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 (12, 14 and 18) and 2,4,6-trichlorobenzoyl chloride.
References
7. (a) Osawa, E.; Goto, H.; Hata, T.; Deretey, E. J. Mol.
Struct. (Theochem.) 1997, 398–399, 229; (b) for the defin-
ition of cluster distance, see: Saunders, M. J. Comput.
Chem. 1991, 12, 645.
8. It is well known that the six-membered ketal of anti-1,3-
diol prefer twist-boat type,10 and the most preferable
conformer of six-membered ketal of anti-1,3-diol (C9,
C11) of model seco-acid 6 was also twist-boat (Fig. 3).
However, the most of the conformation of the corre-
sponding lactone 5 was chair type (Fig. 3). Therefore,
twist-boat conformer has to change to the more unstable
chair conformer before cyclization.
1. Gaumann, E.; Hutter, R.; Keller-Schierlein, W.; Neipp,
L.; Prelog, V.; Zahner, H. Helv. Chim. Acta 1960, 43,
601.
2. Muntwyler, R.; Keller-Schierlein, W. Helv. Chim. Acta
1972, 55, 460.
3. 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. Tetrahedron Lett.
1983, 24, 1311.
Most of the conformation of model compound 8 is
locked as shown in Figure 3, mainly because of hydrogen
bonding between tertiary alcohol at C8 and ether oxygen
of six-membered ketal of C3 and C5 diol. Because of the
locked structure, the reaction point (alcohol at C13 and
terminal carboxylic acid) can not approach each other.
Both conformations of the six-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 sub-
stituents (methyl or phenyl or dimethyl group) on the
six-membered ring of the syn-1,3-diol are far from back-
bone chain, we can conclude that the difference of the
substituents do not affect the backbone conformation.
9. Paterson, I.; Arya, P. Tetrahedron 1988, 44, 253.
10. Clode, D. M. Chem. Rev. 1979, 79, 491.
4. For a previous report related to conformation analysis
for synthetic design; see: Makino, K.; Nakajima, N.;
Hashimoto, N.; Yonemitsu, O. Tetrahedron Lett. 1996,
37, 9077 and references cited therein.
5. 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.
6. Similar conformation (differences of all dihedral angle to
be compared are less than 10 degree) is classified in one
cluster. The conformation of the cluster to be compared
is more similar each other, the conformation distance is
smaller.7 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.