Substituted perhydrofuropyrans: Easy preparation from 2-chloromethyl-3- (2-methoxyethoxy)propene through 3-methylene-1,6-diols

Article abstract of DOI:10.1016/S0040-4039(00)00009-5

The reaction of 2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene (1) with an excess of lithium powder and a catalytic amount of naphthalene (2.5%) in the presence of a carbonyl compound (E¹=R¹R²CO) in THF at -78 to 0°C, followed by treatment with an epoxide [E²=R³R⁴C(O)CHR⁵] at 0 to 20°C leads, after hydrolysis, to the expected unsaturated diols 2. When some compounds 2 (2e-h) are successively hydroborated (BH₃ · THF) and oxidised (33% H₂O₂ and then PCC), the expected perhydrofuropyrans 3e-h are isolated directly. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00009-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1661–1665
Substituted perhydrofuropyrans: easy preparation from
-chloromethyl-3-(2-methoxyethoxy)propene through
-methylene-1,6-diols
2
3
∗
Emilio Lorenzo, Francisco Alonso and Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 18 November 1999; accepted 21 December 1999
Abstract
The reaction of 2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene (1) with an excess of lithium powder and a
1
1
2
catalytic amount of naphthalene (2.5%) in the presence of a carbonyl compound (E =R R CO) in THF at −78
2
3
4
5
to 0°C, followed by treatment with an epoxide [E =R R C(O)CHR ] at 0 to 20°C leads, after hydrolysis, to the
expected unsaturated diols 2. When some compounds 2 (2e–h) are successively hydroborated (BH3·THF) and
oxidised (33% H2O2 and then PCC), the expected perhydrofuropyrans 3e–h are isolated directly. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: lithium; arene-catalysis; dianion synthons; perhydrofuropyrans.
The perhydrofuropyran unit is present in many natural products which show interesting biological
activities. Typical examples are azadirachtin (I, isolated from the seeds of Azadirachta indica, with
1
insect antifeedant and growth inhibitory activities), euplotins A–C (II, isolated from strains of Euplotes
2
crassus, which inhibit cell division or kill marine ciliates), udoteatrial hydrate (III, isolated from Udotea
3
flabellum, with antimicrobial activity against Staphylococcus aureus and Candida albicans), and duroin
(
IV, isolated from the roots of Duroia hirsuta, with allelopathic properties, which inhibits growth of other
4
5
plants), as well as some thymol derivatives (isolated from Arnica sachalinensis).
∗
Corresponding author. Fax: +34-965903549.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00009-5
tetl 16289

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662
6
The preparation of perhydrofuropyran derivatives usually takes place by radical cyclisation, with
7
8
9
cycloadditions, ring-opening processes or intramolecular dehydration reactions being less common.
In all of these processes one of the two heterocyclic rings is previously formed and used for the second
cyclisation. For this reason we thought of the possibility of forming both rings at the same time, starting
from a convenient dihydroxy aldehyde: this methodology has been applied in our laboratories for the
1
0
11,12
generation of perhydrofurofurans, taking advantage of an arene-catalysed lithiation
of chlorinated
1
3
14
isobutylene derivatives at low temperature and working under Barbier-type reaction conditions.
Thus, we describe herein the preparation of substituted perhydrofuropyrans using the above mentioned
methodology.
The reaction of 2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene (1)15 with an excess of lithium pow-
der (1:7 molar ratio) and a catalytic amount of naphthalene (1:0.1 molar ratio, 2.5 mol%) in the presence
1
1 2
of different carbonyl compounds (E =R R CO; 1:0.95 molar ratio) in THF at temperatures ranging from
78 to 0°C for ca. 3.5 h, led to a reaction mixture, which was treated with an excess of an epoxide
−
2
3
4
5
16
as a second electrophile [E =R R C(O)CHR ; 1:3 molar ratio) at 0 to 20°C overnight giving, after
hydrolysis with water, the corresponding unsaturated diols 2a–i (Scheme 1 and Table 1). In the case
of cyclohexene oxide, only the trans-diastereomer was obtained, its stereochemistry being assigned by
1
7
NMR experiments (Table 1, entries 4 and 9).
1
1
2
2
3
4
5
Scheme 1. Reagents and conditions: (i) Li, C10
to 20°C; (iii) H
H
8
cat. (2.5 mol%), E =R R CO, THF, −78 to 0°C; (ii) E =R R C(O)CHR , 0
2
O
The reaction shown in Scheme 1 takes advantage of the different reactivity of the carbon–chlorine
and carbon–oxygen bonds in arene catalysed lithiations.1 Thus, after the first chloro/lithium exchange,
8
19
a functionalised organolithium intermediate V is formed, which by reaction with a carbonyl compound
1
(
E ) gives the expected alkoxide VI. This species can be lithiated at higher temperatures to yield a new
2
dilithiated compound VII, which by final reaction with an epoxide (E ) affords the dialkoxide VIII,
precursor of the diol formed.

1
663
Table 1
Preparation of unsaturated diols 2
The transformation of some diols 2 into the corresponding perhydrofuropyrans 3 was carried out by
simple reactions (Scheme 2 and Table 2). Successive hydroboration–oxidation with hydrogen peroxide
under basic conditions (through the triol IX) and final oxidation with PCC (through compound X), gave
the expected compounds 3e–h. When α-methylstyrene oxide was used as the second electrophile, a ca.
1:1 diastereomeric mixture was obtained (Table 2, entry 1 and footnote d). The cis stereochemistry of the
fused rings in compounds 3 was assigned unequivocally by NOE experiments.
Scheme 2. Reagents and conditions: (i) BH3·THF, 0°C; (ii) 33% H
2 2 2 2
O , 3 M NaOH, 0°C; (iii) PCC, CH Cl , 0°C

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Table 2
Preparation of perhydrofuropyrans 3
As a conclusion, we have described herein a simple methodology which allows the straightforward
preparation of perhydrofuropyrans through the corresponding unsaturated diols, this procedure being a
new approach to this heterocyclic moiety.
Acknowledgements
This work was generously supported by the DGICYT (no. PB94-1514 and PB97-0133) from the
Spanish Ministerio de Educación y Cultura (MEC). E.L. thanks the MEC for a predoctoral grant.
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