An expedient synthesis of 2,5-disubstituted-3-oxygenated tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2009.08.114

Single enantiomer 2,5-disubstituted-3-oxygenated tetrahydrofurans are synthesized in as little as four steps from a commercially available epoxide. The key steps are homoallylic alcohol epoxidation, palladium-catalysed alkoxy-carbonylation-lactonisation and Mitsunobu inversion. The protocol is applied to the formal total syntheses of (+)-kumausallene, (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol and the core of lytophilippine A.

Full text of DOI:10.1016/j.tetlet.2009.08.114

Tetrahedron Letters 50 (2009) 6318–6320
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An expedient synthesis of 2,5-disubstituted-3-oxygenated tetrahydrofurans
*
Caroline L. Nesbitt, Christopher S. P. McErlean
School of Chemistry, The University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Single enantiomer 2,5-disubstituted-3-oxygenated tetrahydrofurans are synthesized in as little as four
steps from a commercially available epoxide. The key steps are homoallylic alcohol epoxidation, palla-
dium-catalysed alkoxy-carbonylation–lactonisation and Mitsunobu inversion. The protocol is applied
to the formal total syntheses of (+)-kumausallene, (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol
and the core of lytophilippine A.
Received 13 July 2009
Revised 10 August 2009
Accepted 28 August 2009
Available online 2 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The 2,5-disubstituted-3-oxygenated tetrahydrofuran unit is
present in many marine natural products. Conspicuous examples
include the C19 lipid diols 1 and 2 isolated from the southern
Australian brown algae Notheia anomala, and (+)-trans-deacetylku-
mausyne (3) isolated from the Japanese red algae, Laurenia nippo-
nica (Fig. 1).1,2 This structural unit also appears as part of more
complex ring systems such as the bicyclo[3.3.0]octane system of
(À)-kumausallene (4), in which each ring constitutes a 2,5-disub-
stituted-3-oxygenated tetrahydrofuran.3 It is noteworthy that nat-
ural products containing both the syn and anti stereochemical
relationship across the ether linkage (cf. 1 and 2) and both the
syn and anti relationship between the C2 substituent and the C3
oxygen (vide infra), as well as members representing both enantio-
meric series (cf. 2 and 3) have been isolated.4 The stereochemical
variety around such a small core has stimulated much interest in
the biosynthesis and the total synthesis of these natural products.5
Previous routes to stereochemically defined 2,5-disubstituted-
3-oxygenated tetrahydrofurans have included a cascade Prins
cyclisation–pinacol rearrangement–Baeyer–Villiger sequence,6
intramolecular conjugate additions,7 acyl radical cyclisations,8 cyc-
lodehydrations,9 biotransformations10 and ring contractions.11
These approaches rely on chiral pool materials such as arabinose,12
the requisite enediols could be generated from commercial benzyl
glycidyl ether 9, which is available in both enantiomeric forms
(Scheme 1). The absolute stereochemistry of the C5 position of
the products (using tetrahydrofuran numbering) would be dictated
by the starting material, and the relative stereochemistry across
the tetrahydrofuran ring could be controlled using either a directed
reduction of an intermediate b-hydroxy ketone or an asymmetric
epoxidation of an intermediate homoallylic alcohol.
Our initial efforts focused on the directed reduction route as
Boukouvalas et al. successfully employed a similar strategy in their
synthesis of (À)-trans-kumausyne.13 The desired b-hydroxy ketone
was envisaged to arise from the nucleophilic opening of 9 with a
suitable acyl anion equivalent of acrolein. As such, the protected
cyanohydrins 10 and 11 were synthesised in the standard fash-
ion.20 Despite exploring the use of several bases (KHMDS, LiHMDS),
solvents (toluene, THF), Lewis acid additives and temperature com-
binations, the desired epoxide ring-opening could not be effected
(Scheme 2). Given that 11 has been used to effect the ring-opening
of epichlorohydrin,21 we reasoned that the epoxide 9 was not
suitably electrophilic enough to engage in a reaction with the
malic acid,13 -glucose,14 diethyl tartrate15 and
D L-galactono-1,4-lac-
tone16 for controlling the absolute stereochemistry. Whilst each of
these routes gives access to at least one stereoisomer of the 2,5-
disubstituted-3-oxygenated tetrahydrofuran unit, we wished to
uncover a flexible, divergent route that would deliver all configura-
tional isomers. The recent report by Britton and co-workers17 of
their aldol-based strategy to uncover such a general synthetic route
has prompted us to disclose our own efforts in the area.
A concise route to single diastereomers of 2,5-disubstituted-3-
oxygenated tetrahydrofurans involves the palladium-catalysed
alkoxy-carbonylation of dihydroxy alkenes.18,19 We envisaged that
* Corresponding author. Tel.: +61 2 9351 3970; fax: +61 2 3951 3329.
E-mail address: C.McErlean@chem.usyd.edu.au (C.S.P. McErlean).
Figure 1. 2,5-Disubstituted-3-oxygenatedtetrahydrofuran-containingnatural prod-
ucts.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.114

C. L. Nesbitt, C. S. P. McErlean / Tetrahedron Letters 50 (2009) 6318–6320
6319
Scheme 1. Retrosynthetic analysis.
Scheme 3. Divergent synthesis of compounds 16 and 17.
jected to Wittig olefination to give 18 as a mixture of geometric
isomers (Scheme 4). The secondary alcohol was protected to give
silyl ether 19. Hydrogenation of the alkene with concomitant
hydrogenolysis of the benzyl group gave the diol 20, which is an
advanced intermediate in Wang’s synthesis of 1.25 This work,
therefore, constitutes a formal synthesis of ent-1.
Scheme 2. Attempted reaction of acyl anions with epoxide 9.
The remaining (2S,3R,5S), (2R,3S,5S), (2R,3S,5R) and (2S,3R,5R)
isomers are available through inversion of the C3 alcohol. As an illus-
tration, 16 was reduced to the corresponding lactol and subjected to
Wittig olefination to give the known alcohol 219 (Scheme 5). Alcohol
21 was then converted into the C3 epimer 22 under standard
Mitsunobu conditions. The (2S,3R,5S)-2,5-disubstituted-3-oxygen-
ated tetrahydrofuran moiety in 22 contains an anti relationship be-
tween the C2 substituent and C3 oxygen and corresponds to the core
of the marine natural product lytophilippine A.26
resonance stabilised anions of the deprotonated cyanohydrins.
Therefore we prepared and investigated methoxyallene 12 as a
more reactive acyl anion equivalent.22 Disappointingly, the potas-
sium, lithium and copper-based anions of this reagent also failed
to undergo coupling to benzyl glycidyl ether 9, even in the pres-
ence of a Lewis acid (MgBr2, BF3ÁOEt2, or Sc(OTf)3). Our attention
therefore turned to the epoxide-based approach.
(S)-Benzyl glycidyl ether 9 was reacted with vinylmagnesium
bromide to give the corresponding homoallylic alcohol 13 in excel-
lent yield (Scheme 3). Whilst this compound could be subjected to
a vanadium-catalysed asymmetric epoxidation,23 we chose to use
it as a point of divergence. As such, compound 13 was subjected
to a non-selective meta-chloroperbenzoic acid epoxidation to give
14 as a ca. 1:1 mixture of diastereomers. The diastereomeric mix-
ture of epoxides was reacted with dimethylsulfonium methylide to
give the corresponding enediols 15 in quantitative yield.24 Com-
pound 15 was then subjected to the palladium-catalysed alkoxy-
carbonylation conditions described by Semmelhack18 to give the
In summary, we have disclosed an expedient route to all
possible stereoisomers of the 2,5-disubstituted-3-oxygenated tet-
rahydrofuran ring system from commercially available (R)- and
known bicyclic-c-lactones 16 and 17, which were readily sepa-
rated by flash chromatography.8,19 Compound 16 contains a
(2S,3S,5S) and compound 17 contains a (2R,3R,5S)-2,5-disubsti-
tuted-3-oxygenated tetrahydrofuran moiety in a protected form.
Performing the same sequence on the enantiomeric (R)-benzyl
glycidyl ether would give the enantiomeric (2R,3R,5R) and
(2S,3S,5R)-2,5-disubstituted-3-oxygenated tetrahydrofurans. As
compound 16 corresponds to an advanced intermediate in Evan’s
synthesis of kumausallene,8 the current work constitutes a concise
formal synthesis of (+)-kumausallene.
Compound 17 has the same relative stereochemical arrange-
ment (but opposite absolute stereochemistry) found in the marine
algal metabolite 1. As such, 17 was reduced to the lactol and sub-
Scheme 4. Formal synthesis of ent-1.

6320
C. L. Nesbitt, C. S. P. McErlean / Tetrahedron Letters 50 (2009) 6318–6320
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Scheme 5. Inversion of the C3 alcohol.
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kumausallene, ent-1 and the core of lytophilippine A.
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Supplementary data
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Supplementary data associated with this article can be found, in
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oxygenated tetrahydrofuran unit rather than the molecule as a whole.
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ˇ
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