Amberlyst-15-catalyzed intramolecular S(N)2' oxaspirocyclization of secondary allylic alcohols. Application to the total synthesis of spirocyclic ethers theaspirane and theaspirone

Article abstract of DOI:10.1016/S0040-4039(00)00396-8

A variety of substituted 1-oxaspiro[4.4]non-6-ene. 1-oxaspiro[4.5]dec-6- ene, 6-oxaspiro[4.5]dec-1-ene and 1-oxaspiro[5.5]undec-7-ene systems have been prepared by utilizing Amberlyst-15-catalyzed intramolecular S(N)2' oxaspirocyclizations of secondary allylic alcohols under mild reaction conditions in quantitative yields. This oxaspirocyclization was applied to the total synthesis of theaspirane and theaspirone from β-ionone in five steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00396-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3415–3418
Amberlyst-15-catalyzed intramolecular SN20 oxaspirocyclization
of secondary allylic alcohols. Application to the total synthesis of
spirocyclic ethers theaspirane and theaspirone
Jenn-jong Young,∗ Liarng-jyur Jung and Kuang-ming Cheng
Institute of Preventive Medicine, National Defense Medical Center, PO Box 90048-700 Sanhsia, Taipei, Taiwan 237, ROC
Received 4 February 2000; revised 2 March 2000; accepted 3 March 2000
Abstract
A variety of substituted 1-oxaspiro[4.4]non-6-ene, 1-oxaspiro[4.5]dec-6-ene, 6-oxaspiro[4.5]dec-1-ene and 1-
oxaspiro[5.5]undec-7-ene systems have been prepared by utilizing Amberlyst-15-catalyzed intramolecular SN20
oxaspirocyclizations of secondary allylic alcohols under mild reaction conditions in quantitative yields. This
oxaspirocyclization was applied to the total synthesis of theaspirane and theaspirone from β-ionone in five steps.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Amberlyst-15; SN20 oxaspirocyclization; secondary allylic alcohols; total synthesis; theaspirane; theaspirone.
Numerous methods are available for the syntheses of allylic oxaspirocycle systems such as 11–4 (Fig.
1). In the preceding paper,5 we reported that allylic oxaspirocycles are readily accessible by Amberlyst-
15-catalyzed intramolecular SN20 oxaspirocyclization of tertiary allylic alcohols with high yields and
easy work-up features. These transformations are synthetically interesting since the allylic oxaspirocyclic
products obtained have a structure very similar to naturally occurring norisoprenoid spiroethers, such as
theaspiranes and vetispirane, which are known aroma components in tea and vanilla, respectively.
Fig. 1.
∗
Corresponding author. Fax +886 2 26725934.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00396-8
tetl 16676

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The application of Amberlyst-15-catalyzed intramolecular SN20 oxaspirocyclization of tertiary ally-
lic alcohols to natural product synthesis has two limitations. First, 1-oxaspiro[4.4]non-6-ene and 6-
oxaspiro[4.5]dec-1-ene systems can hardly be prepared by the method previously reported5 because
the tertiary allylic alcohols cannot be obtained from the corresponding 2-cyclopentenone when treated
with methyllithium. Second, only a few natural products have alkyl substitution at the 7-position of 1-
oxaspiro[4.5]dec-6-ene systems and at the 8-position of 1-oxaspiro[5.5]undec-7-ene systems.
In this report, we demonstrate that the route for Amberlyst-15-catalyzed intramolecular SN20 oxaspi-
rocyclizations of secondary allylic alcohols can also be applied to the syntheses of allylic oxaspirocycles
in high yields, even in cases including steric hindered tertiary nucleophile (Scheme 1). The total synthesis
of theaspirane and theaspirone6 has been achieved via oxaspirocyclization as the key step (Scheme 4).
Scheme 1.
Synthesis of the requisite starting materials of secondary allylic alcohols 6–13 for oxaspirocyclization
was accomplished as outlined in Scheme 2. Enones 22–25, obtained from a reaction of the Normant
Grignard reagent7 with the vinylogous ester 3-ethoxy-2-cyclohexen-1-one and 3-ethoxy-2-cyclopenten-
1-one, were oxidized to form the corresponding esters 26–29 (Jones reagent, acetone, 0°C, then CH2N2,
diethyl ether, 0°C). The alcohols 22–25 and esters 26–29 were reduced to secondary allylic alcohols
6, 8, 10 and 12 and hydroxyesters 30–33 (NaBH4, CeCl3·7H2O, MeOH)8 in high yields, respectively.
The resulting hydroxyesters 30–33 were converted to the corresponding tertiary alcohols 7, 9, 11 and
13 in quantitative yields by treatment with methyllithium in THF at –40°C. The reducing reactions and
methyllithium addition reactions mentioned here gave requisite reaction products, which were used in a
further reaction without any purification.
Scheme 2. (a) NaBH4, CeCl3·7H2O, CH3OH; (b) CH3Li/diethyl ether, THF, −40°C

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All the secondary allylic alcohols 6–13 underwent SN20 oxaspirocyclization under Amberlyst-
15-catalyzed9 conditions to produce the corresponding 1-oxaspiro[4.4]non-6-enes 14 and 15,
1-oxaspiro[4.5]dec-6-enes 16 and 17, 6-oxaspiro[4.5]dec-1-enes 18 and 19, and 1-oxaspiro[5.5]undec-
7-enes 20 and 21 (Scheme 1). However, the cyclization rate (kc) in the secondary allylic alcohol system
is much slower than that in the tertiary allylic alcohol system. On the other hand, in the case of a
six-membered ring formation with steric hindered nucleophile, the elimination rate (ke) is comparable to
the cyclization rate (kc) (Scheme 3). Therefore, the competing elimination products were accompanied
with 19 and 21 even at −20°C. Except for 19 and 21, all other oxaspirocycle products obtained by this
method gave cyclization products only and in quantitative yields.
Scheme 3.
Scheme 4 details the total synthesis of theaspirane 3 and theaspirone 2. The α,β double bond of β-
ionone 34 was selectively reduced by triphenyltin hydride10 to give 35. The allylic methylene group
within the six-membered ring was oxidized at room temperature to form a carbonyl group by using 70%
tert-butyl hydroperoxide and catalytic amounts of chromic anhydride,11 and a CeCl3–NaBH48 reduction
of the enone and ketone provided the required diol 36. The secondary allylic alcohol 36 underwent SN20
oxaspirocyclization under Amberlyst-15-catalyzed conditions to produce theaspirane 3, and after allylic
oxidation under previous conditions to give theaspirone 2. Spectral data of the product were identical to
those of the theaspirone reported in the literature.3
Scheme 4. (a) Ph3SnH, benzene; (b) CrO3, t-BuOOH, CH2Cl2; (c) NaBH4, CeCl3·7H2O, CH3OH; (d) Amberlyst-15, CHCl3,
−20°C
Acknowledgements
We thank the National Science Council (NSC86-2113-M-016-003) of the Republic of China and IPM-
NDMC (Grant No. IPM-870503) for financial support.

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