Highly efficient synthesis of medium-sized lactones via oxidative lactonization: Concise total synthesis of isolaurepanf

Article abstract of DOI:10.1039/b919673k

A catalytic amount of TEMPO in the presence of PhI(OAc)₂ effected oxidative lactonization of 1,6- and 1,7-diols, directly affording seven- and eight-membered lactones, respectively, in good yields. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b919673k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly efficient synthesis of medium-sized lactones via oxidative
lactonization: concise total synthesis of isolaurepan†
Makoto Ebine, Yuto Suga, Haruhiko Fuwa* and Makoto Sasaki
Received 7th July 2009, Accepted 13th October 2009
First published as an Advance Article on the web 26th October 2009
DOI: 10.1039/b919673k
A catalytic amount of TEMPO in the presence of PhI(OAc)2
effected oxidative lactonization of 1,6- and 1,7-diols, directly
affording seven- and eight-membered lactones, respectively,
in good yields.
in oxidative lactonization of a,w-diols in recent years. There are a
number of precedents that describe oxidative lactonization of 1,4-
and 1,5-diols, although most of the reported examples utilized
meso-diols. In contrast, there are only a few specific examples for
oxidative lactonization of seven- and eight-membered lactones5
presumably because of the increased enthalpic and entropic
penalties associated with their formation.6 Thus, the development
of a practical and efficient method for oxidative lactonization of
a,w-diols remains a significant challenge for organic chemists.
Herein we report that oxidative lactonization of 1,6- and
1,7-diols using a catalytic amount of TEMPO and PhI(OAc)2
as stoichiometric oxidant7 proceeds efficiently to provide syn-
thetically useful seven- and eight-membered lactones, respec-
tively, in good yields.8 The remarkable efficiency of the
TEMPO/PhI(OAc)2-mediated oxidative lactonization strategy
was highlighted by its successful implementation to a concise total
synthesis of ( )-isolaurepan.9,10
Piancatelli, Margarita, and co-workers have reported that
TEMPO/PhI(OAc)2 oxidizes alcohols to carbonyl compounds in
CH2Cl2 at room temperature.7 Moreover, primary alcohols can
be selectively oxidized in the presence of secondary alcohols
under these conditions. Forsyth et al. have reported the synthesis
of d-lactones by TEMPO/PhI(OAc)2 oxidation of 1,5-diols.3j
Based on these precedents, we investigated the scope of the
TEMPO/PhI(OAc)2-mediated oxidative lactonization8 by using
various substrates with or without conformational constraint
(Table 1). In contrast to the previous synthesis of 211 that
relied on Yamaguchi lactonization12 of the corresponding hydroxy
acid using a high-dilution technique, the TEMPO/PhI(OAc)2-
mediated oxidative lactonization directly afforded 2 from 1,6-diol
1 in 93% yield under non-high-dilution conditions (0.1 M) (entry
1). Even under a higher concentration (0.3 M) and on a large
scale, 2 was isolated in 83% yield after single recrystallization,
and the formation of dimer or higher oligomers was not observed
(entry 2). Hence we were able to synthesize >15 grams of 2 in
a single experiment. Importantly, 2 is a versatile intermediate in
the synthesis of marine polycyclic ethers.13 A variety of 1,6-diols
3, 5, 7, 9, 11, 13, and 15 could be cleanly oxidized under the
TEMPO/PhI(OAc)2 conditions to afford the respective seven-
membered lactones 4, 6, 8, 10, 12, 14a,b, and 164n in good to
excellent yields (entries 3–10).‡ Oxidative lactonization of 1,6-diol
17 required some optimization. Treatment of 17 with 10 mol%
of TEMPO and 2.5 equiv of PhI(OAc)2 in CH2Cl2 (0.1 M, room
temperature) gave the desired lactone 18 in 40% yield (entry 11).
Increasing both the amount of the reagents and the concentration
of the reaction mixture was beneficial, giving 18 in 69% yield
(entry 12). Thus, it seems that TEMPO/PhI(OAc)2-mediated
oxidative lactonization is generally applicable to the synthesis
Lactone is a common structural motif widely found in biologically
active natural products and pharmaceuticals. In addition, a
number of synthetic methods for functionalization of lactones
are currently available, making them especially useful synthetic
intermediates for the preparation of cyclic ethers.1 Thus, the
development of practical synthetic methods for lactones continues
to be an important and fundamental research in organic synthesis.2
A variety of methods for the synthesis of medium-sized lactones
via the formation of the ester linkage have been reported, which
generally involve activation of an w-hydroxy acid precursor
(Scheme 1, strategy A). However, w-hydroxy acids are often
prepared from differentially protected a,w-diols via multi-step syn-
thesis including oxidations and protective group manipulations.
In contrast, the synthesis of lactones via oxidative lactonization of
a,w-diols represents a more direct and step-economical strategy
due to the fact that oxidation and lactonization occur in a
single flask and that protecting group chemistry is not necessary
(Scheme 1, strategy B).3,4 In fact, there has been growing interest
Scheme 1 Schematic presentation of lactonization strategies for the
synthesis of medium-sized lactones
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences,
Tohoku University, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555,
Japan. E-mail: hfuwa@bios.tohoku.ac.jp
† Electronic supplementary information (ESI) available: Representative
experimental procedure and spectroscopic data for all newly synthesized
products. See DOI: 10.1039/b919673k
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Table 1 Oxidative lactonization of various a,w-diols
Entry
1a
Diol
Lactone
Yield%
93
1
2
2b
3a
83
95
3
4
4a
98
5
7
9
6
5a
85
62
8
6a
10
7c
8a
76
54
11
13
12
9a
100 (14a:14b = 51 : 49)
14a
14b
16
10a
63
15
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Table 1 (Contd.)
Entry
11a
Diol
Lactone
Yield%
40
17
18
12d
13a
69
67
19
21
20
22
14a
80
a TEMPO (10 mol%), PhI(OAc)2 (2.5 equiv), CH2Cl2 (0.1 M), room temperature. b TEMPO (20 mol%), PhI(OAc)2 (2.2 equiv), CH2Cl2 (0.3 M), room
temperature. c TEMPO (10 mol%), PhI(OAc)2 (2.5 equiv), CH2Cl2 (0.5 M), room temperature. d TEMPO (30 mol%), PhI(OAc)2 (5 equiv), CH2Cl2 (0.5 M),
room temperature.
of seven-membered lactones from 1,6-diols. We were pleased
to find that oxidative lactonization of 1,7-diol 19 proceeded
to afford eight-membered lactone 20 in good yield (entry 13),
which should be useful as an intermediate for the synthesis of
eight-membered unsaturated cyclic ether Laurencia metabolites, as
exemplified by (+)-laurencin.14 However, 1,7-diol 21 did not give
the corresponding eight-membered lactone; instead the hydroxy
aldehyde 22 was isolated in 80% yield (entry 14).
The synthesis commenced with allylation of 1-heptanal to give
homoallylic alcohol 24. Olefin cross-metathesis15,16 of 24 with
3-buten-1-ol afforded olefin 25 as a 1.6 : 1 mixture of E/Z isomers,
which was hydrogenated to deliver diol 26 in 53% overall yield.17
Treatment of diol 26 with 10 mol% of TEMPO and 2.5 equiv
of PhI(OAc)2 in CH2Cl2 (0.1 M) at room temperature directly
afforded seven-membered lactone 27 in 73% yield. Introduction
of a propyl side chain was achieved via the intermediacy of
a lactone-derived enol phosphate. Thus, enolization of lactone
27 with KHMDS in the presence of (PhO)2P(O)Cl generated
the corresponding enol phosphate, which without isolation was
alkylated using an organocopper reagent.18 The resulting enol
ether 28 was sensitive to hydrolysis during chromatographic
purification. Thus, upon isolation, 28 was immediately treated with
TMSOTf/Et3SiH to furnish ( )-isolaurepan (23) in 74% overall
The effectiveness of our developed TEMPO/PhI(OAc)2-
mediated oxidative lactonization strategy was demonstrated in
a concise total synthesis of ( )-isolaurepan (23) (Scheme 2).
1
yield from 27 as a single diastereomer. The H, 13C NMR, and
HRMS spectra of synthetic 23 matched those reported in the
literature.9,10 The present total synthesis proceeded in only six steps
from 1-heptanal with an overall yield of 29%, which constitutes
the most concise and high-yielding synthesis hitherto reported.
In summary, we have developed an efficient method for the
synthesis of medium-sized lactones based on the TEMPO/
PhI(OAc)2-mediated oxidative lactonization of a,w-diols, which is
operationally simple and cost effective and proceeds cleanly even
under high concentration conditions without the formation of
dimer or higher oligomers. In addition, the TEMPO/PhI(OAc)2-
oxidative lactonization strategy alleviates protective group chem-
istry as well as separate oxidation steps. These features highlight
the efficiency and practicality of the oxidative lactonization
strategy, being suitable even for multi-gram scale preparation
of synthetically useful medium-sized lactones. The remarkable
efficiency of the synthesis of ( )-isolaurepan demonstrates the
Scheme 2 Total synthesis of ( )-isolaurepan. Reagents and conditions:
(a) allylMgCl, THF, 0 ◦C; (b) 3-buten-1-ol, Grubbs’ 2nd-generation
catalyst, CH2Cl2, 40 ◦C; (c) H2, Pd/C, EtOAc, room temperature, 53%
(three steps); (d) TEMPO (10 mol%), PhI(OAc)2 (2.5 equiv), CH2Cl2
(0.1 M), room temperature, 73%; (e) KHMDS, (PhO)2P(O)Cl, HMPA,
THF, -78 ◦C; then n-PrMgBr, CuI, Me2S, -30 ◦C; (f) TMSOTf, Et3SiH,
CH2Cl2, 0 ◦C, 74% (two steps).
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power and usefulness of the oxidative lactonization strategy in
the synthesis of medium-sized cyclic ethers.
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Acknowledgements
We thank Mr. Kazuya Ishigai for his contributions to the early
stage of this work. This work was supported in part by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Notes and references
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