Synthesis of bicyclic tetrahydrofurans from linear precursors using manganese(III) acetate

Article abstract of DOI:10.1039/c5ob01091h

We have recently developed methodology based on oxidative radical reactions for the synthesis of [3.3.0]-bicyclic lactones containing both cyclopentanes and γ-lactams along with application of this methodology to the synthesis of natural products and complex molecular architectures. Herein we report an extension of this methodology to the synthesis of oxygen heterocycles including bicyclic bis-lactones.

Full text of DOI:10.1039/c5ob01091h

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Synthesis of bicyclic tetrahydrofurans from linear
precursors using manganese(III) acetate†
Cite this: DOI: 10.1039/c5ob01091h
Received 30th May 2015,
Accepted 5th August 2015
Anne-Caroline Chany, Léo B. Marx and Jonathan W. Burton*
DOI: 10.1039/c5ob01091h
www.rsc.org/obc
We have recently developed methodology based on oxidative
radical reactions for the synthesis of [3.3.0]-bicyclic lactones con-
taining both cyclopentanes and γ-lactams along with application
of this methodology to the synthesis of natural products and
complex molecular architectures. Herein we report an extension of
this methodology to the synthesis of oxygen heterocycles includ-
ing bicyclic bis-lactones.
The tetrahydrofuran (THF) moiety is present in a vast array of
biologically active natural products including: the polyketides,
the acetogenins, halogenated natural products from Laurencia
1
,2
species, and numerous terpenes. As a result the develop-
ment of new methodology for the synthesis of THFs, and
related 5-membered oxygen heterocycles, is an on-going and
3
important aspect of modern synthetic organic chemistry.
Recently we have developed methodology based on oxidative
4
radical reactions for the synthesis of [3.3.0]-bicyclic lactones
5
6
containing both cyclopentanes and γ-lactams along with
Fig. 1 Proposed mechanism of formation of [3.3.0]-bicyclic γ-lactones.
application of this methodology to the synthesis of natural
products and complex molecular architectures. Herein we
report an extension of this methodology to the synthesis of
6
,7
8,9
5
-membered oxygen heterocycles containing bicyclic bis-
6
nates, we were aware that malonyl radicals such as 2 are cap-
lactones with up to four stereocentres. In accord with our
1
2
5
,6
todative in nature and, as such might be prone oxidation to
the corresponding oxocarbenium ions prior to cyclisation.
The initial substrates we selected for study were the term-
inal and phenyl-substituted olefins 7a and 7c as we had
demonstrated that the corresponding substrates, in the all
carbon series, could be successfully converted into [3.3.0]-
previous work, we proposed that exposure of substrates such
as 1 to a transition metal oxidant could generate the corres-
ponding malonyl radical 2, which would undergo 5-exo-trig
cyclisation presumably via the pre-transition state assembly 3
in accord with the Beckwith–Houk model of 5-exo-trig radical
1
0,11
cyclisation, to give the adduct radical 4 (Fig. 1).
Oxidation
5
,9
bicyclic γ-lactones under oxidative conditions.
These sub-
of the so formed adduct radical with concomitant C–O bond
formation would deliver the dioxocarbenium ion 5 which gives
the desired [3.3.0]-bicyclic γ-lactone 6 on hydrolysis. As in our
study of the cyclisation of radicals derived from amidomalo-
strates, and all of the substrates in the paper were prepared by
O–H insertion into the corresponding diazo-malonates accord-
ing to the procedure described by Hatakeyama and co-workers
see ESI†).
Exposure of the dimethyl malonate 7a to two equivalents of
3
d,13
(
1
4,15
the one electron oxidant manganese(III) acetate
in the pres-
Department of Chemistry, Chemistry Research Laboratory, Mansfield Road, Oxford,
OX1 3TA, UK. E-mail: jonathan.burton@chem.ox.ac.uk
ence of one equivalent of copper(II) triflate in acetonitrile at
0 °C, according to our previous work, gave the corresponding
3.3.0]-bicyclic γ-lactone 8a in 81% yield (Table 1, entry 1).‡
4
[
†
Electronic supplementary information (ESI) available: Experimental details,
characterisation data and NMR spectra of new compounds. See DOI: 10.1039/
c5ob01091h
The corresponding di-tert-butyl malonate 7b cyclised with
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Table 1 Initial cyclisation studies
Fig. 2 Plausible pre-transition state assemblies for formation of major
and minor diastereomers relating to Table 2.
1
2
Entry
Substrate
R
R
Yield (%)
dr
1
2
3
4
5
a
b
c
d
e
Me
tBu
Me
tBu
Me
H
H
Ph
Ph
Et
81
83
—
—
14 : 1
16 : 1
2 : 1
a
b
b
b
92
a
above. This is a result of the allylic substituents having a prefer-
ence for the pseudo-equatorial position in the chair-like tran-
sition state so as to minimise both allylic strain and 1,3-diaxial
interactions. The modest selectivity exhibited in the cyclisation
62
a
50
a
Combined isolated yield of mixture of diastereomers.
Diastereomeric ratio (dr) refers to the mixture of diastereomers at the
b
1
lactone stereocentre measured from the crude
diastereomer shown.
H
NMR; major of substrates 9a,b,d and e is in keeping with the chair-like pre-
3
transition state assembly where R occupies a pseudo-equatorial
3
position (Fig. 2, TSmaj). However the preference for R to occupy
16
a pseudo-equatorial position is determined by allylic strain; if
3
R
occupies a pseudo-axial position it would suffer only very
similar efficiency (Table 1, entry 2). Using the phenyl-substi-
tuted alkenes 7c and 7d gave the corresponding [3.3.0]-bicyclic
lactones 8c and 8d in good yield and with high diastereo-
control at the lactone bearing stereocentre (major diastereomer
shown, Table 1, entries 3 and 4).§,¶ In keeping with previously
minimal 1,3-diaxial interactions with one of the lone pairs of the
oxygen atom of the forming THF (TSmin).k With much larger
substituents (9c and f), the corresponding lactones 10c,f were
formed with high levels of diastereoselectivity (Table 2, entries 3
and 6). In all cases, the [3.3.0]-bicyclic γ-lactones were formed in
synthetically useful yields.
We next moved to investigate cyclisation reactions of homo-
allylic-substituted substrates 11 (Table 3). Cyclisation of such
substrates would give access to THFs carrying 2/5-substituents
5
reported results in the all carbon series, cyclisation of ethyl-
substituted alkene 7e gave the product 8e in reduced yield and
with lower diastereoselectivity and hence we focussed our
attention on substrates bearing a terminal alkene or styrene.
Given the successful cyclisation of substrates 7, we turned
our attention to substrates carrying a substituent at the allylic
position (Table 2). With relatively small substituents (9, R = Me,
CH CO tBu), the corresponding lactones 10 were formed with
moderate diastereocontrol (Table 2, entries 1, 2, 4 and 5).§,¶ In
the cyclisation of 5-hexenyl radicals, allylic substituents fre-
quently impart higher levels of diastereocontrol than exhibited
–
positions that are frequently substituted in THF-containing
1
,2
3
natural products.
Cyclisation of the substrates 11a–d
(
Table 3, entries 1–4) gave the product bicyclic lactones 12a–d
2
2
in good yields with pleasing levels of diastereocontrol.§,¶ With
the phenyl-substituted alkenes 11e–h the corresponding pro-
ducts 12e–h were formed as a mixture of three diastereomers.§
For all the products 12, the relative configuration of the major
Table 2 Cyclisations with allyl-substituted malonates
Table 3 Cyclisations with homoallyl-substituted malonates
3
2
a
4
2
a
b
Entry
Substrate
R
R
Yield (%)
dr
3 : 1
3.6 : 1
22 : 1
4.6 : 1c
3.2 : 1
28 : 1
Entry
Substrate
R
R
Yield (%)
dr
b
b
b
b
1
2
3
4
5
6
a
b
c
d
e
f
Me
CH
iPr
Me
CH
iPr
H
H
H
Ph
Ph
Ph
73
76
73
92
69
92
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Me
iPr
Ph
CHvCH
Me
iPr
Ph
CHvCH2
H
H
H
H
Ph
Ph
Ph
Ph
96
94
80
86
66
61
70
80
6.1 : 1
5.7 : 1
7.5 : 1
5 : 1
2.8 : 1
3.2 : 1
2.6 : 1
2.8 : 1
2
CO
CO
2
tBu
tBu
2
2
2
g
h
a
Combined isolated yield of mixture of diastereomers; major
diastereomer shown. Diastereomeric ratio (dr) refers to the mixture of
diastereomers at the R -bearing sterocentre measured from the crude
b
3
a
Combined isolated yield of mixture of diastereomers; major
b
1
c
H NMR. Ratio is given as major diastereomer : sum of minor diastereomer shown. Ratio is given as major diastereomer : sum of
diastereoisomers; detailed dr = 6.7 : 1 : 0.7 : 0.4.
minor diastereomers.
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Table 4 Cyclisations to form bicyclic bis-lactones
Conclusions
In summary, we have reported a mild and operationally simple
synthesis of bicyclic THFs and bicyclic bis-lactones in syntheti-
cally useful yields and with good levels of diastereocontrol.
Application of this methodology to the synthesis of natural
products and related targets is on-going.
3
2
a
b
Entry
Substrate
R
R
Yield (%)
dr
1
2
3
4
a
b
c
H
iPr
H
H
H
Ph
Ph
77
73
62
77
—
Acknowledgements
24 : 1
9.6 : 1
9.6 : 1
We thank the European Commission (FP7-PEOPLE-2012-
IEF-329876) and the EPSRC for financial support. We thank
the analytical sections of our Department for their excellent
support.
d
iPr
a
Combined isolated yield of mixture of diastereomers >90% pure.
Ratio is given as major diastereomer : sum of minor diastereomers.
b
diastereromer of the products was in keeping with the Beck-
Notes and references
1
0,11
with–Houk model
for 5-hexenyl radical cyclisation. The
‡
Control experiments indicated that both manganese(III) acetate and copper(II)
triflate were required for efficient product formation – see ESI† for details.
In some cases other components were present in the crude reaction mixtures
that may be other diastereomers but these components could not be
levels of stereocontrol are in keeping with related cyclisations
5
and examples from our group.
§
Having investigated the cyclisation of ether substrates we
briefly turned to investigate cyclisation of ester substrates 13 characterised.
(
Table 4). Gratifyingly, under our previously optimised con- ¶The relative configuration of the major diastereomer of the product lactones
1
was assigned on the basis of H NMR nOe experiments or by analogy – see ESI†
ditions efficient cyclisation occurred to give the bicyclic bis-
lactones 14 with good levels of diastereocontrol, although it
was not always possible to isolate the products in pure form.
Many of the small densely functionalised products formed
in the above cyclisation reactions contain differentiated oxygen
functional groups which can be independently manipulated
for details. The relative configuration of a small number of the minor diastereo-
1
mers was also assigned by H NMR nOe experiments.
kBoat-like transition states are also possible.
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7
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