Efficient and flexible synthesis of chiral γ- And δ-lactones

Article abstract of DOI:10.1039/b801514g

An efficient and highly flexible synthesis for chiral γ- and δ-lactones with high enantiomeric purity is described (>99% ee and 57-87% overall yield). The protocol involves alkylation of chiral 1,2-oxiranes with terminally unsaturated Grignard reagents. Subsequent oxidative degradation (OsO₄-Oxone) of the terminal double bond from chiral alk-1-en-5-ols and alk-1-en-6-ols affords 4- or 5-hydroxy acids and γ- and δ-lactones after acidic workup. The flexibility and efficiency of the protocol is illustrated by the synthesis of several alkanolides and alkenolides, hydroxy fatty acids and dihydroisocoumarins. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b801514g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient and flexible synthesis of chiral c- and d-lactones†
Andreas Habel and Wilhelm Boland*
Received 28th January 2008, Accepted 1st February 2008
First published as an Advance Article on the web 10th March 2008
DOI: 10.1039/b801514g
An efficient and highly flexible synthesis for chiral c- and d-lactones with high enantiomeric purity is
described (>99% ee and 57–87% overall yield). The protocol involves alkylation of chiral 1,2-oxiranes
with terminally unsaturated Grignard reagents. Subsequent oxidative degradation (OsO4–Oxone) of the
terminal double bond from chiral alk-1-en-5-ols and alk-1-en-6-ols affords 4- or 5-hydroxy acids and c-
and d-lactones after acidic workup. The flexibility and efficiency of the protocol is illustrated by the
synthesis of several alkanolides and alkenolides, hydroxy fatty acids and dihydroisocoumarins.
Here we report a fast and flexible strategy for the highly enan-
Introduction
tioselective synthesis (≥99% ee) of c- and d-lactones, that can also
c- and d-Lactones or natural products with c- and d-lactone
substructures are widespread and many of them display pro-
nounced biological activities as attractants for pollination1 and
seed germination stimulants.2 c- and d-Lactones also act as
pheromones,3 antiseptics,4 allergens,5 or even as cardiotonic
compounds.6 Lactones are important flavor and aroma con-
stituents and are extensively used as food additives and in
perfumery. For example, 4-butylbutanolide occurs in the flavour
of apricot, raspberry, hazelnut, strawberry, tea, and exhibits a
sweet, creamy dairy flavour with fatty and oily coconut nuances
that is recognised down to 7 ppb. A similar low threshold
displays 4-octylbutanolide, a characteristic flavour component
of apricot, beer, peach, pineapple, rum, and strawberry.7–9 Also
microorganisms are an important source for c- and d-lactones.10,11
In almost all cases, the biological activity of the compounds
is intrinsically linked to their configuration, which underlines the
necessity for efficient and flexible routes to chiral lactones. Since
the lactone moiety represents a bifunctional structural element in
which both functions can be selectively elaborated, lactones also
represent valuable building blocks for synthesis.
provide hydroxy fatty acids and substituted dihydroisocoumarins.
Results and discussion
The synthetic approach is illustrated in Scheme 1. Key steps of the
protocol are the (i) regioselective alkylation of terminal oxiranes
with terminally unsaturated Grignard reagents, and the (ii)
chemoselective oxidative cleavage of the resulting terminally unsat-
urated secondary alcohols to hydroxy acids, which can be cyclized
to c- and d-lactones by brief treatment with acid during work-up.
The chemoselective oxidation of the terminal double bond without
simultaneous oxidation of the secondary alcohol30 is the most im-
portant improvement of the sequence and avoids protective group
manipulations. Unlike previous protocols using ozonization31,32 or
osmoylation33 followed by oxidative cleavage of intermediates, the
current method proceeds as a single step operation.
Enantiomerically pure alkanolides are readily available by a
multitude of biotransformations using lipases,12–16 Baeyer–Villiger
oxidases,17,18 amidases,19 nitrilases20 or yeasts.21 Typical asym-
metric syntheses22 utilise the enantioselective hydrogenation23
or reduction24 of c-ketoacids, the ring-opening of chiral ter-
minal epoxides with 1-morpholino-2-trimethylsilyl acetylene,25
silver(I)triflate catalysed intramolecular additions of hydroxyl or
carboxyl groups to double bonds,26 or asymmetric Bayer–Villiger
oxidations using planar-chiral bisflavin catalysts.27
Scheme 1 Protocol for the synthesis of chiral alkanolides.
Highly functionalized alkanolides can be obtained by a Re-
formatsky type of reaction of a-hydroxy ketones with indium
enolates.28 For a recent review see ref. 29.
Due to the ease, efficiency and compatibility of the hydrolytic ki-
netic resolution (HKR) of terminal epoxides with other functional
groups following the Jacobson protocol, a broad range of the chiral
oxiranes is accessible with high ee (>99%).34,35 Their subsequent
alkylation with terminally unsaturated Grignard reagents in the
presence of Cu(I)36 proceeds exclusively at C(1) and provides the
corresponding terminally unsaturated secondary alcohols in high
yields and with complete retention of the ee of the starting oxirane
(>99%).
Department of Bioorganic Chemistry, Max Planck Institute for Chemi-
cal Ecology, Hans-Knoell-Str.8, 07745-Jena, Germany. E-mail: boland@
ice.mpg.de; Fax: +49 3641 571200; Tel: +49 3641 571202
† Electronic supplementary information (ESI) available: General exper-
imental, synthesis of substrates and spectra for compounds. See DOI:
10.1039/b801514g
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To generate the different ring sizes of c- and d-lactones,
the terminal oxiranes are alkylated with either 1-propenyl- or
1-butenyl Grignard reagents in the presence of (7–10 mol%)
cuprous iodide. Alternatively, the alk-1-en-5-ols can be obtained
by addition of alkyl-Grignard reagents to 1,2-epoxy-5-hexene 2
(Scheme 2).
groups within the molecule such as alcohols, ethers, aromatic rings,
esters and, most importantly, alkynes, this opens a direct route to
unsaturated lactones and hydroxy acids. For example, (4S,6Z)-
dodecenolide (Scheme 4), previously isolated as major compound
from the fungus Fusarium poae38 and the fungus Sporidiobolus
salmonicolor39 was obtained in 74% overall yield from (S)-1,2-
epoxy-5-hexene 2 via alkynylation with heptynyl lithium and
oxidative cleavage of the terminal double bond followed by
hydrogenation.
Scheme 4 Synthesis of (4S,6Z)-6-dodecen-4-olide.
The alkynylation of the oxirane was achieved according to
Yamaguchi and Hirao40 in the presence of BF3·Et2O at −78 ◦C
and provided the secondary alcohol in 87% isolated yield and
>99% ee.
A second example for an olefinic lactone is outlined in
Scheme 5 illustrating the synthesis of (4R,9Z)-octadec-9-en-4-
olide 21 (micromolide). Micromolide has been identified as the
female sex pheromone of the currant stem girdler Janus integer41
and has been extracted from the stem bark of the Rutaceae
Micromelum hirsutum.42 The compound exhibits potent in vitro
activity against Mycobacterium tuberculosis (H37Rv). Alkylation
of (S)-1,2-epoxy-5-hexene 2 with tridec-4-ynyl magnesium bro-
mide in the presence of Cu(I) afforded the alkynol 10 in 84% yield.
Scheme 2 Alkylation of chiral terminal oxiranes with alkenyl-Grignard
reagents.
The recently reported oxidative cleavage of terminal double
bonds with catalytic amounts of OsO4, promoted by Oxone as
a co-oxidant, allowed a straightforward and direct conversion
of the alk-1-en-4-ols or alk-1-en-5-ols into 3- or 4-hydroxy acids
without concomitant oxidation of the secondary hydroxy group.30
Yields were generally high (81–97%) and the resulting hydroxy
acids could be readily cyclized to the corresponding lactones by
acidic work-up37 (Scheme 3).
Scheme 5 Synthesis of micromolide.
Subsequent oxidation and hydrogenation afforded micromolide
in 64% overall yield in only four steps. A previously reported
synthesis required 11 steps and resulted in an overall yield of
14%.43
Scheme 3 Oxidative cleavage of the terminal double bond.
Unlike previous methods for the oxidative cleavage of olefins,
the procedure of Travis et al. proceeds directly to carboxylic acids,
without the intermediacy of 1,2-diols. The whole sequence does
not affect the chiral centre of the secondary alcohol, and (R)-
tridec-1-en-5-ol yielded (R)-c-dodecalactone 14 with complete
retention of configuration. Accordingly, the configuration at C(2)
of the starting oxirane is preserved in the lactone target as shown
by chiral gas chromatography of the intermediates and products.
Since the system OsO4–Oxone tolerates additional functional
Since the system OsO4–Oxone also tolerates aromatic systems,
the methodology can be also applied to the synthesis of aromatic
lactones. Chiral 3,4-dihydroisocoumarins, previously identified
as ant trail pheromones,44 were recently synthesized by lateral
lithiation of (S)-4-isopropyl-2-(o-tolyl)oxazoline and alkylation
with aromatic or aliphatic aldehydes in two operations and 40–
90% overall yield.45
Following our protocol, the (3S)-3-hexyl-isochroman-1-one
(Scheme 6), can be prepared from commercial starting materials in
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manipulations of the molecule prior to the conversion into the
lactone or hydroxy acid.
Conclusions
In conclusion, we present a general and efficient enantioselective
synthesis for alkanolides, alkenolides and hydroxy fatty acids
(>99% ee) that utilizes only simple and readily available reagents.
The procedure provides the target compounds in only three steps,
high overall yields and very high enantiomeric excess (≥99%,
depending on the ee of the starting oxirane).
Scheme 6 Synthesis of 3,4-dihydroisocoumarins.
Acknowledgements
two steps and 87% overall yield and 99% ee as shown in Scheme 6
without the need for a kinetically controlled lactonization for
enhancement of the ee as described in ref. 45.
Financial support of this work by the Deutsche Forschungsge-
meinschaft, SFB 436 “Metal Mediated Reactions Modeled After
Nature” is gratefully acknowledged.
By modification of the work-up procedure of the oxidative
degradation, chiral hydroxy fatty acids also become available
since the ring-closure of lactones (>C6) is no longer spontaneous.
For example, (S)-12-hydroxyoctadecanoic acid was obtained in
only two steps (Scheme 7) from (S)-1,2-epoxyoctane and dec-9-
enyl magnesium bromide. With acetylenic epoxides or Grignard
reagents, the sequence can also be applied to generate unsaturated
hydroxy acids.
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>99
>99
>99b
>99
>99b
>99
>99
70
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71
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64
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57
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(5S)-Tridecan-5-olide
(4S,6Z)-Dodec-6-en-4-olide
(4R,9Z)-9-Octadecen-4-olide
(S)-3-Hexyl-isochroman-1-one
(12S)-12-Hydroxy-octadecanoic acid
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