Stereoselective routes to aryl substituted γ-butyrolactones and their application towards the synthesis of highly oxidised furanocembranoids

Article abstract of DOI:10.1039/c1ob05113j

Titanium chelate addition of aryl nucleophiles to cyclopropyl aldehyde 6 followed by a tin-catalyzed one-pot retro-aldol, acetalisation and lactonisation sequence afforded cis and trans γ-aryllactone acetals. A γ-furyllactone derived by this approach was

Full text of DOI:10.1039/c1ob05113j

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Stereoselective routes to aryl substituted c-butyrolactones and their
application towards the synthesis of highly oxidised furanocembranoids†
Allan Patrick G. Macabeo, Andreas Kreuzer and Oliver Reiser*
Received 21st January 2011, Accepted 8th March 2011
DOI: 10.1039/c1ob05113j
Titanium chelate addition of aryl nucleophiles to cyclopropyl
aldehyde 6 followed by a tin-catalyzed one-pot retro-aldol,
acetalisation and lactonisation sequence afforded cis and
trans c-aryllactone acetals. A c-furyllactone derived by this
approach was further transformed in two steps to model
compounds for the oxidised northeastern sectors of selected
Pseudopterogorgia diterpenoids.
Highly substituted g-butyrolactone motifs are profusely present in
many synthetic intermediates and biologically active structures.1
In general, their enantiomeric purity and absolute configura-
tion play a significant role on their purported pharmacolog-
ical properties.2 Thus, much effort has been invested in their
asymmetric synthesis.3 Among the derivatives thus far reported,
less attention has been devoted to the stereoselective synthesis
of trans and especially, cis g-aryl- or heteroarylbutyrolactones.4
Such lactone-based synthons may serve as intermediates for the
Fig. 1 Representative natural products that can be derived from
synthesis of highly oxidised furanocembranoids (e.g. 1–3) and
g-aryllactones.
lignan natural products (e.g. 4) (Fig. 1).5
We previously reported that Hosomi–Sakurai allylation of furan
ester 5 derived cyclopropyl aldehyde 6 affords trans lactones 7
with high diastereoselectivity following the Felkin–Ahn paradigm
as the operating addition pathway.6 A useful alternative would
appear to be the addition of nucleophiles through a substrate-
controlled Cram chelate addition pathway that should lead to the
corresponding cis-lactones. In this study, we wish to disclose the
addition of aryl- and heteroarylltitanium nucleophiles to 6 leading
to either cis- or trans-lactones 9, which appear to be useful building
blocks towards the synthesis of 1–4 (Scheme 1).
We initiated our experiments by screening furyl nucleophiles
taking into consideration the sensitive nature of the methyl oxalate
moiety in 6 under basic nucleophilic conditions. Initial attempts
to add several different 2-furyl metal reagents (ArCeCl2, ArCuCl,
ArZnCl) alone or in combination with BF3·OEt2 to aldehyde
6 were unsuccessful (Scheme 2). Either decomposition or no
Scheme 1
reaction of the starting material was observed. Organotitanium
reagents display high chemo- and diastereoselectivity towards
aldehydes in comparison to other carbonyl functionalities and are
considered as “well-behaved reagents” because of their ability to
mitigate chemical reactivity and basicity.7 Nevertheless, reaction
of the 2-furyltitanium reagent 8a with 6 was also unsuccess-
ful, however, when BF3·OEt2 was additionally employed, the
desired furyl transfer was finally achieved to give rise to 10a
Institut fu¨r Organische Chemie, Universita¨t Regensburg, Universita¨tsstrasse
31, Regensburg, D-93053, Germany. E-mail: Oliver.Reiser@chemie.
uni-regensburg.de; Fax: +49 9419434621; Tel: +49 9419434631
† Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra. CCDC reference numbers 809453
and 809454. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob05113j
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Scheme 2
(>90% conversion). While 10a can be isolated, due to its sensitive
nature we opted to directly convert it to the corresponding
lactone 9a through a retro-aldol and lactonisation sequence upon
saponifying the oxalylic ester, making use of the 1,2-donor–
acceptor relationship8 in the cyclopropane ring (Scheme 2).
Previously, we reported Ba(OH)2·8H2O and Otera stannoxanes6,9
as effective reagents to carry out this transformation for allylated
derivatives of 6. Treatment of 10a with Ba(OH)2·8H2O however,
failed to give the expected furyllactone carbaldehyde. Gratifyingly,
stannoxane 11a furnished the desired lactone acetal 9a, albeit in
only 23% overall yield based on 6. Screening of other stannoxane
derivatives revealed 11c to be more effective, improving the overall
yield of the two-step sequence from 6 to 9a to 40% (Table 1,
entry 1–3).
allylsilanes/BF3·OEt2,6 and the excellent oxygen-chelating capa-
bilities of titanium reagents make us propose a cyclic Cram
chelate-type featuring a rather unusual 8-membered titanium
complex (Scheme 3, pathway I).11 The aryl nucleophile is delivered
externally from the sterically less hindered face of the carbonyl
group, giving rise to 10c–g as the major diastereomer.
Subsequently, a representative number of other aryltita-
nium reagents, being readily prepared by dehydrolithiation
or dehalolithiation of aryl derivatives followed by titanation
with ClTi(OPri)3, were tested for the synthesis of lactones 9
(Scheme 2).10 Besides 2-thienyl (entry 4) and phenyl (entry 5),
alkoxy substituted aryl groups (entries 6–9) being especially
relevant towards naturally occurring compounds such as 4 could
be successfully introduced. However, aryltitanium nucleophiles
bearing substitutions at the ortho-position, e.g. those derived from
2-bromoanisole and 2-bromotoluene, were not amenable with this
reaction sequence, which is most likely due to steric hindrance.
The stereochemistry of 9a–g was confirmed through 2D-
NOESY correlation experiments and X-ray analysis of 9c (see
supporting information). Thus, it was revealed that the diastere-
oselectivity of this reaction sequence was greatly influenced by
the type of aryl nucleophile being used. While the 2-furyltitanium
8a gave rise predominantly to the trans-lactone 9a (86 : 14), the
aryl substituted lactones 9c–9g were obtained with moderate to
excellent cis-selectivity (3 : 1 to >99 : 1), demonstrating for the first
time that addition of nucleophiles to 6 can ultimately lead to cis-
lactone of type 9 as the major products.
Scheme 3
The cis-selectivity observed in the formation of 9c–9g with
aryltitanium/BF3·OEt2 reagents, contrasting the high trans-
selectivity achieved in the corresponding transformations with
In contrast, the syn-selectivity observed with furan titanate
8a results through the formation of an incipient bond between
the furyl nucleophile and the electrophilic aldehyde carbon while
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Table 1 g-Aryl and allyl lactone synthesis from cyclopropane aldehyde, 6
Entry
1
Organotitanium nucleophile
Aldehyde
Lactonea
Yieldb
23c
cis : trans ratioe
6
14 : 86
2
3
4
29d
40
38
6
54 : 46
5
6
7
8
9
ent-6
45
38
40
33
37
>99 : 1
ent-6
ent-6
ent-6
6
82 : 18
74 : 26
76 : 24
92 : 8
10
6
29f
6 : 94
a Major diastereomer shown. b Unless otherwise stated, 11c was used as catalyst. Overall yield in two steps. c 11a was used. d 11b was used. e Based on
relative integrals in the 1H NMR spectrum. f Lactonisation was carried out with Ba(OH)2·8H2O.
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the oxygen atom in the furan ring is coordinated with titanium,
favoring the formation syn addition product 10a (Scheme 3,
pathway II).
sation of 6 with allylsilanes in substrate scope, but also offers for
the first time a reversal of stereochemistry. Thus, cis-disubstituted
g-aryl-b-methyl acetal lactones with good diastereoselectivity in
enantiomerically pure form can be obtained, which compares well
with previously reported methods.3–4
The poor diastereoselectivity achieved with the thienyl
nucleophile 8b could be explained by the weaker coordination
ability of sulfur to titanium, thus resulting in no preference
either for pathway I or II. The lower diastereoselectivity for
oxygenated aryltitanium reagents leading to 9d–9g compared
to 9a might reflect different degrees of internal delivery of
the nucleophile via coordination of titanium to the oxygen
substituents in the aryl rings. In agreement with this proposal
is the highly selective addition of allyltitanium 8h to 6 (Table 1,
entry 10), leading to 13 by directed delivery of the allyl nucle-
ophile via a Zimmerman–Traxler-like transition state (Scheme 3,
pathway III).
Lactone 9a seemed to be a suitable precursor to study the synthe-
sis of the northeastern segments of diterpenoids 1 and 2 Scheme 4).
Initial attempts to perform oxidative transformations on the furan
ring using a number of methods known for that moiety, i.e.
singlet oxygen oxidation, mCPBA or Jones oxidation12 to furnish
a g-hydroxybutenolide were unsuccessful. Using bromine13 in
methanol, however, afforded the 2,5-dimethoxy-2,5-dihydrofuran
14 in 75% yield, albeit as a mixture of three diastereomers in
a 1 : 1 : 2 ratio, from which 14c could be separated by chro-
matography. From the mixture of 14a and 14b the former was
obtained in pure form by crystallisation and its structure could be
assigned unambiguously by X-ray structural analysis. The major
diastereomer 14c was heated with Bredereck’s reagent14 to install
the a-dimethylaminomethylene handle, furnishing 15 in good yield
(81%). The model precursor product thus obtained satisfies the
1S,2S,3S (and 6S) configurations required in furanocembranoids
1 and 2.
Acknowledgements
A.P.G.M. is grateful to the Deutscher Akademischer Austausch-
dienst (DAAD) for a graduate fellowship.
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