A new method for the synthesis of medium- and large-sized carbocycles

Article abstract of DOI:10.1055/s-1999-2696

A new synthetic method for medium and large-sized carbocycles has been developed. An acyclic compound having an olefin moiety and a 3- (methylthio)allyl acetate moiety at each of the terminal positions was designed as a cyclization precursor. The correspo

Full text of DOI:10.1055/s-1999-2696

LETTER
647
A New Method for the Synthesis of Medium- and Large-Sized Carbocycles
Keiichi Masuya,a Keiji Tanino,*b Isao Kuwajima*c
a Department of Chemistry, Tokyo Institute of Technology, Meguro, Tokyo 152-8551, Japan
b Division of Chemistry, Graduate School of Science, Hokkaido University, Kita-ku, Sapporo 060-0810, Japan
c The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
Received 19 February 1999
Abstract: A new synthetic method for medium and large-sized car-
OSiR'3
bocycles has been developed. An acyclic compound having an ole-
fin moiety and a 3-(methylthio)allyl acetate moiety at each of the
terminal positions was designed as a cyclization precursor. The cor-
responding allyl cation intermediate, which was generated by treat-
ment with EtAlCl2, underwent cyclization via an intramolecular
addition reaction. The ring size of the product, which depends on
the reaction site of the allyl cation, can be controlled by changing
the nucleophilicity of the terminal olefin moiety.
OSiR'3
MeS
MeS
OAc
EtAlCl2
O
+
R
X
+
R
X
O
MeS
R
MeS
R
Key words: cyclization, allylcation, Lewis acid, vinyl sulfide,
X
X
homoallylsilane
not observed
Scheme 2
Medium- and large-sized carbocycles are an important
class of compounds which occur in a range of natural and
unnatural products, and an increasing number of cycliza-
tion techniques for these carbocycles have been devel-
oped. In the biosynthesis of terpenoids, an intramolecular
addition reaction of a carbon-carbon double bond to an al-
lyl cationic moiety is the most important process for con-
structing medium- and large-sized carbocycles.1 From a
synthetic viewpoint, however, use of this type of cycliza-
tion reaction may suffer from competition between the
(n)-membered and (n+2)-membered rings.2,3
SMe
SMe
SMe
EtAlCl2
(1.1 eq)
(1)
CH2Cl2
-23 ~ 0 °C
OAc
Cl
not observed
SMe
Cl
1a
2 33%
SMe
SMe
EtAlCl2
(1.1 eq)
+
(2)
CH2Cl2
-23 °C
OAc
Me3Si
3 4%
4 81%
1b
+
n
n+2
+
bered chloride 2, while six-membered product 4 was pre-
dominantly obtained from allylsilane 1b.
or
+
R
R
R
In order to understand the different behavior between 1a
and 1b, PM3 calculations7 on the cationic intermediates
were performed. The results indicated that eight-mem-
bered intermediate B, which involves the conjugation of
the methylthio group and the double bond, is 9.6 kcal/mol
more stable than six-membered intermediate C. Accord-
ingly, an eight-membered compound would be produced
under thermodynamic control, while cyclization to a six-
membered ring is kinetically favored. Selective formation
of six-membered product 4 from 1b is, therefore, attribut-
able to the high nucleophilicity of the allylsilane moiety.
Next, we designed cyclization precursors 1c,8 1d,6 and 1e6
with a view to increasing the chemical yield of the eight-
membered product. We envisioned that the neighboring-
group participation of the internal acetoxy group would
stabilize the eight-membered tertiary cation intermediate
and control the stereochemistry of the product (Figure 2).
Scheme 1
On the other hand, we have reported a highly regioselec-
tive [3+2] cyclopentanone annulation reaction using a 3-
(methylthio)-2-siloxyallyl cationic species (Scheme 2).4 It
is noteworthy that the initial C-C bond formation between
an olefin and the allyl cationic intermediate predominant-
ly occurs at the g-position of sulfur.5
The directing effect of sulfur in controlling the reaction
site of an allyl cation led us to develop a new synthetic
method for medium- and large-sized carbocyclic com-
pounds. In order to estimate the directing effect of sulfur,
allyl acetates 1a and 1b having a terminal olefin moiety
were designed as cyclization precursors.6 Interestingly,
the ring size of the products depends on the nature of the
olefin moiety (Eq 1 and Eq 2). Thus, treatment of 1a with
EtAlCl2 resulted in selective formation of eight-mem-
Synlett 1999, No. 5, 647–649 ISSN 0936-5214 © Thieme Stuttgart · New York

648
K. Masuya et al.
LETTER
SMe
SMe
SMe
SMe
+
H
O
+
+
O
+
MeS
1c
5
Me
B
C
O
A
+
189.58 kcal/mol
199.20 kcal/mol
O
Me
Cl-
The Heat of Formation for Cyclization Intermediates B and C
Calculated by PM3 Method
Scheme 3
Figure 1
Since several attempts for constructing a nine-membered
carbocycle from a homologue of 1c proved fruitless, an
aromatic ring was incorporated with an allyl cation pre-
cursor in order to facilitate a cyclization reaction.
AcO
SMe
SMe
SMe
AcO
AcO
SMe
OAc
OAc
OAc
Under the influence of EtAlCl2, 6a underwent cyclization
to afford nine-membered compound 7a as a single isomer
(Eq 4). Ten- to twelve-membered products 7b, 7c, and 7d
were also obtained, albeit in much lower stereoselectivi-
ties, from the corresponding diacetates 6.8 In these cases,
reactions in moderately dilute solutions led to better
chemical yields.
1c
1d
1e
SMe
SMe
O
AcO
HO
AcO
1c
1d
1e
+
Me
or
O
Cl
Figure 2
MeS
AcO
MeS
AcO
OAc
EtAlCl2
(1.3 eq)
(4)
Cl
CH2Cl2
0.05 ~ 0.005 M
-45 ~ -23 °C
( )n
( )n
Although the reactions of 1d and 1e with EtAlCl2 led to
complex results, 1c underwent smooth cyclization to give
cyclooctene 5 as a single diastereomer in good yield (Eq
3). However, the cis relationship between the OAc group
and chlorine, which was established by X-ray crystallo-
graphic structure determination, ruled out the possibility
of neighboring-group participation as depicted in Figure
2.
6a: n = 1
6b: n = 2
6c: n = 3
6d: n = 4
7a 68% (single isomer)
7b 74% (1:1 mixture)
7c 58% (3:1 mixture)
7d 72% (1:1 mixture)
Although the functional groups of the cyclization prod-
ucts would have advantages for natural product synthesis,
a tertiary chloride moiety is not always suitable for further
functionalization. We designed another type of cycliza-
tion precursor having a homoallylsilane moiety10 with a
view to trapping a tertiary cation intermediate by 1,2-hy-
dride shift promoted by a silyl group (Eq 5). Since a ho-
moallylsilane has much lower nucleophilicity than the
corresponding allylsilane, the reactions of 8a6 and 8b8 re-
sulted in selective formation of eight-membered products.
AcO
SMe
AcO
SMe
EtAlCl2
(1.3 eq)
(3)
CH2Cl2
-45 °C
OAc
Cl
5 86%
1c
In order to clarify the origin of the high yield as well as the
complete stereoselection, we performed PM3
calculations7 on the allyl cationic species. The results sug-
gested that an interaction between the internal acetoxy
group and the terminal cationic carbon plays an important
role in fixing the conformation by forming a seven-mem-
bered ring (Scheme 3). The axial orientation of the side
chain, which is attributable to an allylic strain,9 would be
advantageous for the cyclization reaction, and successive
C-C bond formation and introduction of a chloride ion
would give 5 stereoselectively.
R
SMe
R
SMe
R
SMe
EtAlCl2
(1.3 eq)
(5)
CH2Cl2
0.05 M
-45 ~0 °C
+
OAc
H
SiMe3
SiMe3
8a: R = H
8b: R =OAc
9a 50%
9b 82%
Synlett 1999, No. 5, 647–649 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Method for the Synthesis of Medium- and Large-Sized Carbocycles
649
(5) It is reported that the C-C bond formation reaction between an
enol silyl ether and a 1-(phenylthio)allyl cation occurs at the
g-position of sulfur: Hunter, R.; Simon, C. D. Tetrahedron
Lett. 1986, 27, 1385.
(6) These types of cyclization precursors were prepared in four
steps from the corresponding alkyl iodide as shown below.
The geometry of the double bond was determined by
observation of NOE between the olefinic methyne proton and
the methylthio group.
In conclusion, a new synthetic method for medium- and
large-membered carbocycles was developed by using in-
tramolecular cyclization reaction of a 3-(methylthio)allyl
cationic species. It is noteworthy that the reaction site of
the allyl cation can be controlled by the nucleophilicity of
the terminal olefin moiety. The functional groups of the
cyclization products such as a vinyl sulfide moiety would
have advantages for natural product synthesis.
1) BuLi
2) R-I
1) BuLi
2) BrCH2CO2Et
SMe
SO2Tol
SMe
SO2Tol
SMe
Acknowledgement
CH2CO2Et
SO2Tol
R
R
This work was partially supported by Grants from the Ministry of
Education, Science, Sports, and Culture of the Japanese Govern-
ment. K.M. thanks JSPS for a predoctoral fellowship.
1) DIBAL
2) Ac2O
DMAP
SMe
R
SMe
R
DBU
CO2Et
OAc
References and Notes
For alkylation reactions of methylthiomethyl p-tolyl sulfone,
see: Ogura, K.; Ohtsuki, K.; Nakamura, M.; Yahata, N.;
Takahashi, K.; Iida, H. Tetrahedron Lett. 1985, 26, 2455.
(7) (a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209.
(b) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 211.
(1) (a) Natural Products Chemistry; Nakanishi, K.; Goto, T.; Ito,
S.; Natori, S.; Nozoe, S., Eds.; University Science Books: Mill
Valley, CA, 1974; 1983; Vol. 1 and 3. (b) Cane, D. E. in
Biosynthesis of Isoprenoid Compounds; Porter, J. W.;
Spurgeon, S. L., Eds.; J. Wiley & Sons: New York, 1981; Vol.
1. (c) West, C. A. in Biosynthesis of Isoprenoid Compounds;
Porter, J. W.; Spurgeon, S. L., Eds.; J. Wiley & Sons: New
York, 1981; Vol. 1.
(2) For an example of an intramolecular cyclization reaction of
allyl cation giving a large-sized carbocycle: Gassman, P. G.;
Riehle, R. J. J. Am. Chem. Soc. 1989, 111, 2319.
(3) For selected examples of intramolecular cyclization reactions
of allyl cation: (a) Johnson, W. S. Acc. Chem. Res. 1968, 1, 1.
(b) Kitagawa, Y.; Hashimoto, S.; Iemura, S.; Yamamoto, H.;
Nozaki, H. J. Am. Chem. Soc. 1976, 98, 5030. (c) Sakane, S.;
Fujiwara, J.; Maruoka, K.; Yamamoto, H. Tetrahedron 1986,
42, 2193.
(4) (a) Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. Synlett
1996, 157. (b) Masuya, K.; Domon, K.; Tanino, K.;
Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 1724. Similar
methylene-cyclopentane annulation could also be effected by
using the substrate having a TMS-methyl group in place of the
siloxy group. Takahashi, Y.; Tanino, K.; Kuwajima, I.
Tetrahedron Lett. 1996, 37, 5943.
(8) These types of cyclization precursors were prepared in three
steps from the corresponding aldehyde as shown below:
SMe
MeS
1) Red-Al
2) I2
iPr3SiCl
imidazole
I
OSiIPr3
SMe
OH
R
60% (2 steps)
SMe
1) tBuLi
Ac2O
Et3N
R
TBAF
2) RCHO
OH
OAc
OSiIPr3
OAc
(9) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(10) Sakurai, H.; Imai, T.; Hosomi, A. Tetrahedron Lett. 1977,
4045.
Article Identifier:
1437-2096,E;1999,0,05,0647,0649,ftx,en;Y04499ST.pdf
Synlett 1999, No. 5, 647–649 ISSN 0936-5214 © Thieme Stuttgart · New York