Stereoselective synthesis of bicyclic lactones by annelation with functionalised orthoesters

Article abstract of DOI:10.1039/b600677a

An efficient two-step annelation of functionalised orthoesters with trimethylsilyloxyfuran derivatives, which delivers suitably decorated bicyclo[3.n.0]lactones in high overall yields and with complete diastereocontrol of up to three contiguous stereocenters, is reported. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b600677a

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COMMUNICATION
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Stereoselective synthesis of bicyclic lactones by annelation with
functionalised orthoesters{
Nuno Maulide and Istva´n E. Marko´*
Received (in Cambridge, UK) 18th January 2006, Accepted 30th January 2006
First published as an Advance Article on the web 14th February 2006
DOI: 10.1039/b600677a
An efficient two-step annelation of functionalised orthoesters
with trimethylsilyloxyfuran derivatives, which delivers suitably
decorated bicyclo[3.n.0]lactones in high overall yields and with
complete diastereocontrol of up to three contiguous stereo-
centers, is reported.
Oxabicyclic and oxatricyclic systems are among Nature’s preferred
building blocks for the elaboration of varied biological activities
Scheme 1 Proposed antithetic analysis of bicyclolactones 4.
through chemical diversity. In particular, the c-butyrolactone/
lactol moiety is a recurrent feature of many naturally occurring
had to be demonstrated, and ii) the ring closure of the initial
substances. Some representative examples are depicted in Fig. 1.1
adducts into the desired bicyclic structures had to proceed
Although approaches to the synthesis of bicyclic lactones have
efficiently. Inspired by the seminal work of Pelter and Asaoka,
been imaginative and numerous,2 there is a continued demand for
who successfully condensed trimethyl orthoformate, acetate and
connective and concise methods for the assembly of these
benzoate with trimethylsilyloxyfuran derivatives,5 we treated 5a
important subunits that can deal with the following issues: (a)
with orthoester 6a, in the presence of substoichiometric amounts of
provide high levels of stereoselectivity, (b) cope with the
zinc chloride (0.7 eq. ZnCl2, CH2Cl2, 278 uC to rt). Pleasingly, the
condensation product 7a, bearing an v-chlorine atom, could be
preparation of a variety of ring sizes and (c) allow an increase in
complexity through introduction of reactive functionalities. In this
isolated in good yields. The crystalline iodinated analogue 7b was
communication, we wish to report some of our preliminary results
also prepared by the same procedure in comparably high yields
in the establishment of such a methodology.
(Scheme 2).
As presented in Scheme 1, we envisioned that a variety of
With adducts 7a and 7b in hand, attention was then focused on
bicyclo[3.n.0]lactones 4 might become readily available through the
the crucial ring closure step.6 Accordingly (Scheme 3), both
annelation of 2-trimethylsilyloxyfuran derivatives
5 by the
functionalised orthoesters 6.3 Although these annelating agents
have been previously condensed with cyclic silyl enol ethers,4 to the
best of our knowledge, this is the first time that such a direct two-
step annelation is envisaged on a silyloxyfuran template.
compounds were separately exposed to the action of tris(trimethyl-
silyl)silane (TTMSS) in refluxing benzene solution containing
catalytic amounts of AIBN.7 Interestingly, whilst chlorinated 7a
was recovered unchanged, its iodinated counterpart 7b smoothly
The success of this synthetic strategy required the fulfilment of
two crucial conditions, namely, i) the viability of the condensation
between extended silyl enol ethers such as 5 and our orthoesters 6
Scheme 2 Initial results on the condensation of trimethylsilyloxy furan
with functionalised orthoesters.
Fig. 1 Selected natural products embodying a c-butyrolactone/lactol
subunit.
Universite´ catholique de Louvain, De´partement de Chimie, 1 Place Louis
Pasteur, B-1348, Louvain-la-Neuve, Belgium.
E-mail: marko@chim.ucl.ac.be; Fax: +32 10/472788; Tel: +32 10/
478773
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b600677a
Scheme 3 Radical-mediated cyclisation of adducts 7a and 7b.
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1200 | Chem. Commun., 2006, 1200–1202

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provided bicyclo[4.3.0]lactone 8a in excellent yield and as a single
diastereomer.
with 5a and 5b (entries 3 and 5).8 However, the ensuing adducts
display a somewhat lower stability than ketals 7a and 7b, which
can complicate their purification and lead to decomposition over
large periods of time. Conversely, most of the products bearing a
dioxolane protecting group are perfectly stable upon chromato-
graphy on silica-gel and can be stored without any noticeable
change of properties.
Encouraged by the efficiency of this process, which constituted
an operationally simple two-step annelation of trimethylsilyloxy
furan 5a, we prepared a range of condensation products, bearing
different tether lengths. The results are collected in Table 1.
Particularly noteworthy is the observation that this conden-
sation reaction is not limited to the use of dioxolane-containing
orthoesters (e.g. 6a and 6b). Indeed, the simpler trialkoxy
orthoester derivatives 6c and 6e also underwent smooth coupling
Table 2 Radical-mediated cyclisations of condensation products 7a
Entry Condensation product Bicyclic lactone
1
Yieldb
c
—
Table 1 Results of the condensation reactions between trimethylsily-
loxy furan derivatives and functionalised orthoestersa
Entry Furan derivative Orthoester
1
Product
Yieldb
75%
2
98%
2
95%
3
88%
3
4
95%
4
72%
47%c
5
6
7
a
65%
90%
97%
5
6
94%
80%
7
86%
a
All reactions performed in the presence of 1.5 eq. TTMSS, 0.15 eq.
AIBN, in refluxing benzene. In all cases, a single diastereomer of the
product was detected in the crude mixture. All yields refer to pure,
Unless otherwise stated, all reactions were carried out in the
presence of 0.7 eq. ZnCl2 in CH2Cl2 with a 5 : 6 ratio of 1 : 1.5,
b
b
from 278 uC to r.t. Yields refer to pure, isolated products.
Reaction performed with 5 eq. TMSOTf as the Lewis acid.
c
c
isolated products. No reaction was observed.
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Albert-Ludwigs-Universita¨t, Freiburg) for providing us with
experimental details for the preparation of 5a and 5b. Financial
support for this work by the Universite´ catholique de Louvain, the
Fonds pour la Recherche dans l’Industrie et l’Agriculture
(F.R.I.A., studentship to N.M.) and Merck, Sharp and Dohme
(Merck Academic Development Award to I.E.M.) is gratefully
acknowledged. N.M. is grateful to the Fond National de la
Recherche Scientifique (F.N.R.S.) for receiving an ‘‘Aspirant
F.N.R.S.’’ research fellowship.
Scheme 4 Complementary routes to diastereomeric lactones 8f and 8g.
It should be noted that, although the yield reported for product
7d, containing a 3-carbon tether (entry 4), is slightly lower than the
remaining examples, the preparation of this compound represents,
to the best of our knowledge, the first example of an intermolecular
condensation employing the Corey OBO-orthoester 6d.9 This
observation is particularly significant as it establishes the latter
compounds as potentially valuable intermolecular acylating agents
rather than mere, inert, protecting groups in synthesis.
Notes and references
1 For a review, see: H. D. Fischer, N. H. Fischer, R. W. Franck and
E. J. Olivier, Progress in the Chemistry of Organic Natural Products,
vol. 38; Springer-Verlag, Vienna, 1979, p. 47.
2 For selected recent examples, see: H. Krawczyk, M. Sliwinski,
W. M. Wolf and R. Bodalski, Synlett, 2004, 1995; G. C. Paddon-
Jones, C. S. P. McErlean, P. Hayes, C. J. Moore, W. A. Konig and
W. J. Kitching, J. Org. Chem., 2001, 66, 7487; R. J. Madhushaw,
C.-L. Li, K.-H. Shen, C.-C. Hu and R.-S. Liu, J. Am. Chem. Soc., 2001,
123, 7427; B. B. Snider, B. Shi and C. A. Quickley, Tetrahedron, 2000,
56, 10127; N. Gathergood and K. Anker Jorgensen, Chem. Commun.,
1999, 18, 1869.
Having secured an efficient access to the halogenated adducts
7a–g, we then turned our attention to their radical-mediated
cyclisation reactions. The results of these experiments are compiled
in Table 2.
Apart from Entry 1, all the ring-forming reactions proceeded in
an efficient manner. Particularly worthy of comment is the
otherwise rare 4-exo-trig cyclisation leading to 8d.10 Indeed, such a
compound embodies the suitably functionalised bicyclo[3.2.0]hep-
tane core present in Pestalotiopsin A 3. These cyclisations appear
to benefit from a moderate Thorpe–Ingold effect induced by the
ketal substituent, which accelerates the ring closure.
3 For reviews on the chemistry of trimethylsilyloxyfuran derivatives, see:
G. Casiraghi and G. Rassu, Synthesis, 1995, 607; S. K. Bur and
S. F. Martin, Tetrahedron, 2001, 57, 3211.
4 I. E. Marko´ and A. Ates, Synlett, 1999, 1033; I. E. Marko´,
J.-C. Vanherck, A. Ates, B. Tinant and J.-P. Leclercq, Tetrahedron
Lett., 2003, 44, 3333. For an application to total synthesis, see:
N. Maulide, J.-C. Vanherck and I. E. Marko´, Eur. J. Org. Chem., 2004,
19, 3962. For elegant uses of other orthoesters, see: C. Huart and
L. Ghosez, Angew. Chem., Int. Ed. Engl., 1997, 36, 634; P. Ding and
L. Ghosez, Tetrahedron, 2002, 58, 1565 and references cited therein.
5 M. Asaoka, N. Sugimura and H. Takei, Bull. Chem. Soc. Jpn., 1979, 52,
1953; A. Pelter, R. Al-Bayati and W. Lewis, Tetrahedron Lett., 1982, 23,
353; A. Pelter, R. Al-Bayati and P. Pardasani, Tetrahedron Lett., 1986,
27, 749; A. Pelter, R. I. H. Al-Bayati, M. T. Ayoub, W. Lewis,
P. Pardasani and R. Hansel, J. Chem. Soc., Perkin Trans. 1, 1987, 4,
717.
6 For related cyclisations, see: S. H. Wagner and I. J. Lundt, J. Chem.
Soc., Perkin Trans. 1, 2001, 780–788; G. A. Molander and D. J. St. Jean,
Jr., J. Org. Chem., 2002, 67, 3861 and references therein. For a recent
example of vinyl radical cyclisation onto a butenolide moiety, see:
J. Robichaud and F. Tremblay, Org. Lett., 2006, DOI: 10.1021/
ol0527328.
7 In stark contrast, orthoesters 6c and 6e do not provide similar adducts
when reacted with silyl enol ethers derived from cyclic ketones.
8 C. Chatgilialoglu, Acc. Chem. Res., 1992, 25, 188.
9 For intramolecular condensations of such orthoesters, see: J.-W. Huang,
C.-D. Chen and M.-K. Leung, Tetrahedron Lett., 1999, 40, 8647;
J. M. Andres, E. M. Munoz, R. Pedrosa and A. Perez-Encabo, Eur.
J. Org. Chem., 2003, 17, 3387 and reference 4d. For the synthesis of
these orthoesters, see: E. J. Corey and N. Raju, Tetrahedron Lett., 1983,
24, 5571.
Importantly, all these cyclisations take place with complete
diastereocontrol, foremost when substituted furan derivatives were
employed in the initial condensation step (entries 6–7). In these
cases, 3 contiguous stereocenters are generated in one step with
. 95% stereoselectivity. Furthermore, as shown in Scheme 4,
adduct 8g, prepared by alkylation of 8b, and cyclisation product 8f
are epimeric at the a-lactone carbon centre (marked with *).11 The
efficient access to both stereoisomers with complete control of their
relative stereochemistry further broadens the scope of this
methodology.
In summary, we have disclosed a concise, two-step annelation
methodology that proceeds with high efficiency and complete
diastereocontrol. Using this protocol, a wide variety of bicy-
clo[3.n.0]lactones 8 can be easily assembled from readily available
trimethylsilyloxyfuran derivatives and functionalised orthoesters,
in high overall yields. Importantly, the added functionality
introduced by the orthoester as a ketal protecting group renders
these bicyclolactones particularly interesting scaffolds for subse-
quent elaboration. Current efforts are now aimed at delineating
the full scope of this original methodology, installing an
enantioselective version and applying it to the synthesis of
biologically relevant substances. The results of these investigations
will be reported in due course.
10 Interestingly, inspection of product 8d reveals it to be the opposite
regioisomer of a formal [2 + 2] cycloaddition of ketene to a dihydrofuran
derivative.
11 The envelope-like topology of these bicyclic systems directs the hydrogen
delivery to the intermediate cyclic radical from the less congested
convex-face. Similarly, methylation occurs from the least hindered,
exocyclic face.
We are grateful to Professor Reinhard Bru¨ckner
(Institut fu¨r Organische Chemie und Biochemie der
1202 | Chem. Commun., 2006, 1200–1202
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