Dianion Methodology for the Construction of Large-Membered Ring Systems: Application to the Synthesis of Muscone.

Article abstract of DOI:10.1016/S0040-4039(00)60824-9

A dianion method for the construction of the macrocycles has been developed and applied to the synthesis of natural fragrance muscone.Conformational analysis of the macrocycle using MM2-Monte Carlo method was carried out to evaluate whether the rationally designed intermediate will readily cyclize.

Full text of DOI:10.1016/S0040-4039(00)60824-9

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Dianion Methodology for the Construction of Large-Membered Ring
Systems: Application to the Synthesis of
Takashi
Yoichi
Haruo
Takeharu
and Yoshimasa
Department of Chemical Engineering, Tokyo Institute of Technology,
Tokyo 152, JAPAN
of Chemistry, Hiroshima University,
Higashihiroshima, Hiroshima 724, JAPAN
Summary: A dianion method for the construction of the macrocycles has been developed and applied to the
synthesis of natural fragrance
analysis of the macrocycle using
designed intermediate will readily
Carlo
method was carried out to evaluate whether the
The most crucial problem in the synthesis of macrocyclic compounds is to have
an efficient method of cyclization.
We have reported a general method for the
con stru ction of
cyanohydrin
to l&membered rings by the intramolecular alkylation of
and have shown the utility of this method in total synthesis of
natural products.2) The dianion cyclization method described herein (Fig-l) involves
the intermolecular alkylation of the dianion 1 with the alkyl dihalide 2. followed by
intramolecular alkylation of the monoanion 3 to give the macrocycle 4. The cyclization
suffers from the competition of a polymerization through the dialkylated product 5
which comes from the intermolecular alkylation of 3 with the alkyl halide 2. In general,
h igh su b strate con cen tration s favor th e in term olecu lar p rocess w h ereas th e
intramolecular process occurs without competition only at low concentrations.
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To circumvent this difficulty, molecular mechanics calculations31
have been
employed to design the synthetic intermediate 3 having an enhanced propensity for
cyclization. We also describe the synthesis of natural fragrance
dianion cyclization methodology.51
by using this
The rate of cyclization may be interpreted in terms of the activation energy and
probability of end-to-end encounters. The activation energy is thought to reflect the
strain energy of the ring to be formed. The probability of the terminal anion and halide
coming close enough to
should decrease as the chain gets longer.61 In terms of
entropy, reduction of the degrees of freedom of internal rotations of the open chain
precursor 3 by introducing double bond should result in partial compensation for the
entropy loss caused by freezing of internal bond rotations upon ring closure. Thus, we
introduce the double bond into the open chain monoanion 8 and/or 9 and select the
position of the double bond where the minimum ring strain will be experienced when
8 and/or 9 approach to the ring shaped transition state. In order to make a prediction
for the location of the double bond, the cyanohydrin ether 8 was selected as a lead
compound. Monte Carlo (MC) random-search method71 was applied to finding the
lower-energy conformers of 6. The structures generated by MC search were energy
minimized by using MM2 force field.81 A total of 47 unique minima were found within
2.4 Kcal/mol of the global minimum. The results of these calculations are shown in
Table-l. Among the lowest 10 energy conformers, torsional angles at
and
methylene groups are oriented in antiperiplanar fashion except for
torsional angle of the 3rd conformer and 13-C 14-C 15 torsional angle of the 4th
conformer. These conformational properties in the lowest energy conformers of 6
suggest that introduction of the trans double bonds at carbons and/or
in 6 show preferable alignments in which
1-C 12
positions would provide the structural features required for the cyclization to
proceed rapidly. Based on the conformational analysis of 6, the dicyanohydrin 7 were
selected as the dianion precursor in which the trans double bond was introduced to the
position equivalent to the
position of

7563
First, we examined the dianion cyclization of
in dioxane (10 was added the protected cyanohydrin 7 (0.86
(10 over 4 h at 80 Removal of the ethoxy
followed by a mild base treatment (2% afforded
To a solution of
(9.5
and the
ditosylate 10 (1.7 mmol) in
ethyl groups
the
11 in 64% overall yield. Then a series of the substrates with no
to compare the tendency
conformational bias toward the cyclization was
for the cyclization of the trans dianion 7 with that of the other substrates. Cyclization of
the saturated derivative 14. which decreases the probability of end-to-end encounters,
with the ditosylate 10 gave the
in 31% overall yield after acid and base
which imposes an extra enthalpic penalty,
treatments. Reaction of the cis derivative
provided the
17 in 37% overall yield in three steps. To enhance the reactivity
stage, the diallyl halides 19 and 20. which also have the
of the intramolecular
two double bonds in the open chain precursors, were subjected to the dianion
cyclization. Comparable results were however obtained. These results that the
introduction of the double bond with the correct configuration at an appropriate
position in the open chain precursor is effective for assisting the formation of the rings
by the dianion.
1 0
EEO
7
0
1)
32%
212%
78%
11
1 2
13
0

7564
conversion of the
11 into
13 was carried out. Selective
followed by tosylation of
reduction of the saturated ketone present in 11 with
the resulting alcohol gave the tosylate 12 in 62% yield. Removal of the
group with
alcohol in 78% yield. Oxidation of the alcohol with
of double bonds with led smoothly to 13
super-hydride provided the
PCC. followed by
in 73% yield.
In summary, we have developed a dianion cyclization method for the construction
rings based on the molecular design of the open chain precursors having
of
a high propensity for cyclization. Other applications of the dianion
for the
synthesis of natural products are currently under investigation.
References and Notes
Author to whom all correspondence should be addressed.
Visiting scientist from Kuraray Co. Ltd., Japan.
Takahashi, T.;
H.; Tsuji, J. Tetrahedron
2005.
Takahashi, ‘I’. “Studies in Natural Products Chemistry, Stereoselective Synthesis (part E)“, Elsevier, 1991,
Vol. 8, p.175.
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Monte Carlo conformational search and MM2 calculations were carried out by
V3.1. We
grateful to Professor W. C. Still for providing a copy of this program. Mohamadi, F.; Richards, N. G. J.;
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The dicyanohydrin 7 was prepared from geranyl acetate as follows.
73% 2)
59%
1) EVE,
th en 120
93%
3)
Cyclizations of the compounds
and 18 were carried out under the same reaction condition that used
for the cyclization of 7 with 10. We also confirmed that yields of the cyclizations were reproducible.
We also examined the cyclization of the ditosylates
i
and ii with the saturated dicyanohydrin 18. Cyclization
of 18 with the
i gave the
in 20% overall yield in three steps. The
ditosylate ii which contained cis double bond, showed no improvement on the cyclization yield (15%).
ii
Takahashi,
K.;
H.; Tsuji, J.; Miura, I.
1983, 24, 3489.
(Received in Japan 24 August 1992)