An efficient synthesis of endo,exo-furofuranone derivatives.

Article abstract of DOI:10.1039/b206150c

The ring openings of 1-acetyl-4-phenyl-3-oxabicyclo[3.1.0]hexane afforded alpha-acetyl-gamma-butyrolactone that underwent a novel diazo-transfer reaction, followed by C-H insertion, to provide a series of endo,exo-furofuranone analogues.

Full text of DOI:10.1039/b206150c

An efficient synthesis of endo,exo-furofuranone derivatives
a
a
b
Nigel A. Swain, Richard C. D. Brown* and Gordon Bruton
a
Department of Chemistry, University of Southampton, Southampton, UK SO17 1BJ.
E-mail: rcb1@soton.ac.uk; Fax: +44 (0) 2380 596805; Tel: +44 (0) 2380 594108
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK CM19 5AW
b
Received (in Cambridge, UK) 27th June 2002, Accepted 30th July 2002
First published as an Advance Article on the web 13th August 2002
The ring openings of 1-acetyl-4-phenyl-3-oxabicyclo-
[
3.1.0]hexane afforded a-acetyl-g-butyrolactones that un-
derwent a novel diazo-transfer reaction, followed by C–H
insertion, to provide a series of endo,exo-furofuranone
analogues.
The furofurans are one of the largest subclass of lignans and
continue to attract substantial interest due to their varied
biological activities. Additionally, the rigid bicyclic frame-
Scheme 3 Reagents and conditions: i, 2,2,6-trimethyl-4H-1,3-dioxin-4-one,
xylenes, 150 °C; ii, Mn(OAc) , Cu(OAc) , KOAc, AcOH, 70 °C.
3
2
1
work of the furofuran(one)s could provide a novel scaffold for
the assembly of libraries for biological evaluation. Conse-
quently, the preparation of structural analogues is of significant
importance.
oxidative cyclisation of b-ketoester 11 successfully provided
the desired cyclopropane 12 in good yield (74%) and excellent
7
diastereoselectivity (trans+cis, 22+1). trans-Lactone 12 was
8
obtained exclusively after recrystallisation. Surprisingly, there
We have recently reported an approach to the endo,exo-
furofuran series 6 that utilised an intramolecular C–H insertion
reaction to close the C1–C2 s-bond (Scheme 1).2 Although
has only been a limited number of similar cyclopropanations to
provide related bicyclo[3.1.0]lactones.9
,3
We envisioned cyclopropane 12 as a key intermediate
towards furofuranone derivatives due to its expected predisposi-
tion to undergo nucleophilic ring opening. Indeed, addition of
soft nucleophiles (e.g. cuprates, thiols, amines) proceeded very
smoothly although opening with alcohols proved more prob-
lematic.1
0,11
We turned our attention to the Lewis acid assisted
openings of cyclopropane 12 in neat methanol but, even at
reflux for 24 h, conversion to the desired product 13 was low.‡
Fortunately, access to a SmithSynthesizer™ microwave re-
actor12 allowed us to investigate a much broader range of
conditions with the conclusion that cyclopropane 12 could be
opened, with methanol, effectively at 120 °C.13 Consumption of
1
2 was observed after just 30 min at this temperature (with a
stoichiometric amount of Zn(OTf) ) to provide desired methyl
ether product 13 and corresponding enol ether 14 (Scheme 4).
2
Scheme 1 Reagents and conditions: i, H
CF CH OCOCF ; iii, p-NO SO , NEt
2
O
2
, AcOH; ii, LiHMDS,
3
2
3
2 6
C
H
4
N
2 3
3
; iv, 2 mol % Rh (OAc)
2
4
.
this original route provided an entry to furofuranones 5 and
furofurans 6, including three lignan natural products, it had
some shortcomings. The initial [2 + 2] cycloaddition reaction4
to form cyclobutanones 1 was low yielding with electron rich
aromatic systems. Furthermore, this same step was not readily
2
Scheme 4 Reagents and conditions: i, MeOH, Zn(OTf) , 120 °C,
microwave radiation.
5
applicable to the enantioselective synthesis of cyclobutanones.
Microwave conditions were not required for benzylic alcohol
additions due to their higher boiling points, and following a
survey of metal triflates and other common Lewis acids,
Mg(ClO ) provided the best results.§ Ultimately, optimisation
4 2
of the conditions allowed opening of 12 to be conducted with
Here we report a new, more robust and higher yielding approach
to furofuranone lignan derivatives 5, centering on the nucleo-
philic ring openings of a cyclopropane intermediate 8 to afford
the key precursors 7 to diazo-lactones 4 (Scheme 2).
three equivalents of the appropriate alcohol, neat, at 120 °C with
1
0 mol% of Lewis acid, providing products 15a–d in excellent
yields with very little enol ether formation (Scheme 5).
Substrates 15a–d proved completely inert to all attempted de-
acetylative diazo-transfer procedures reported in the literature,
despite the fact that such transformations are well pre-
cedented.3 However, a facile and highly reactive one-pot
method was devised that successfully transformed these acetyl-
activated lactones 15a–d to their corresponding a-diazo-
lactones 16a–d in good to excellent yields following the in situ
generation of triflyl azide under phase-transfer catalysis
(Scheme 6).15 Furthermore, these biphasic conditions could find
applications in diazo-transfers to particularly difficult substrates
,14
Scheme 2
6
Our investigation began with acetoacetylation of 1-phenyl-
prop-2-en-1-ol (10) to provide the corresponding acetoacetate
ester 11 in excellent yield (Scheme 3).† Mn(III)-mediated
2
042
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Notes and references
†
Reaction time of 10 min to avoid [3,3] sigmatropic rearrangement of
product.
1
‡
§
Ratio of starting cyclopropane+product = 5+2 ( H NMR).
Although we have not experienced any problem in the handling or heating
of these metal perchlorates, extreme care should be taken when manipulat-
ing them due to their potentially explosive nature.18
1
2
For the latest in a series of lignan reviews, see: R. S. Ward, Nat. Prod.
Rep., 1999, 16, 75.
R. C. D. Brown, C. J. R. Bataille, G. Bruton, J. D. Hinks and N. A.
Swain, J. Org. Chem., 2001, 66, 6719; R. C. D. Brown, C. J. R. Bataille
and J. D. Hinks, Tetrahedron Lett., 2001, 42, 473; R. C. D. Brown and
J. D. Hinks, Chem. Commun., 1998, 1895.
Scheme 5 Reagents and conditions: i, ArCH
C.
2 4 2
OH, 10 mol% Mg(ClO ) , 120
°
3
For a selection of reviews containing examples of cyclisation by metal
catalysed C–H insertion, see: M. P. Doyle, Chem. Rev., 1986, 86, 919;
T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091; M. P. Doyle
and M. A. McKervey, J. Chem. Soc., Chem. Commun., 1997, 983; M. P.
Doyle and D. C. Forbes, Chem. Rev., 1998, 98, 911; A. Padwa and K.
E. Krumpe, Tetrahedron, 1992, 48, 5385; J. Adams and D. M. Spero,
Tetrahedron, 1991, 47, 1765.
4
5
J. B. Falmagne, C. Schmit, J. Escudero, H. Vanlierde and L. Ghosez,
Org. Synth., 1990, 69, 199.
For examples of chiral amide derivatives to effect enantioselective
cyclobutanone formation, see: C. Genicott and L. Ghosez, Tetrahedron
Lett., 1992, 33, 7357.
n
6 J. R. Clemens and J. A. Hyatt, J. Org. Chem., 1985, 50, 2431.
7 For an excellent review on Mn(III)-promoted oxidative cyclisations, see:
B. B. Snider, Chem. Rev., 1996, 96, 339.
Scheme 6 Reagents and conditions: i, NaN
hexane/MeCN (2+1+1), 0 °C; ii, 2 mol% Rh
3
, (Tf)
2
O, Bu
4
NBr, 2 M NaOH/
Cl , rt.
2
(OAc)
4
, CH
2
2
8
The stereochemical assignment of 12 was unambiguously determined
by X-ray crystallography: S. J. Coles and M. B. Hursthouse, personal
communication.
B. B. Snider and B. A. McCarthy, Tetrahedron, 1993, 49, 9447; M. P.
Bertrand, H. O. Hahamat, C. Moustrou and J. M. Surzur, Tetrahedron
Lett., 1989, 30, 331; M. P. Bertrand, H. O. Hahamat, C. Moustrou and
J. M. Surzur, J. Org. Chem., 1989, 54, 5684.
that have previously proved challenging. As expected, the C–H
insertion reactions proceeded rapidly and highly diaster-
eoselectively upon treatment of a catalytic quantity of rhodiu-
9
m(II) acetate dimer to provide furofuranones 17a–d bearing aryl
substituents with an endo,exo-configuration.2
,16
Thus, the
synthesis of series a (Ar = Ph) was complete in 5 steps with
7% overall yield and demonstrates the excellent efficiency of
4
10 N. A. Swain and R. C. D. Brown, unpublished results.
11 For a review on electrophilic cyclopropanes, see: S. Danishefsky, Acc.
Chem. Res., 1979, 12, 66.
this approach. Furthermore, the convergent nature of this route
provides opportunites to assemble diverse sets of structural
furofuran lignan derivatives.
1
1
2 For company details, see: www.personalchemistry.com.
3 For acid and Lewis acid assisted cyclopropane openings in other
unrelated systems, see: W. S. Trahanovsky and N. S. Fox, J. Am. Chem.
Soc., 1974, 96, 7968; T. Kurihara, K. Nasu and Y. Adachi, J.
Heterocycl. Chem., 1983, 20, 81; D. L. Boger and C. W. Boyce, J. Org.
Chem., 2000, 65, 4088.
In summary, we have achieved a concise and diaster-
eoselective synthesis of a series of endo,exo-furofuranone
analogues. Significant contributions include the microwave
assisted optimisation of alcohol additions to cyclopropane 12
under Lewis acidic conditions and development of a highly
effective diazo-transfer protocol to afford a-diazo-g-butyr-
olactones. Future work in this area will focus on an asymmetric
synthesis of g-butyrolactones and potential furofuranone de-
rivatives.
1
4 D. F. Taber, R. J. Herr, S. K. Pack and J. M. Geremia, J. Org. Chem.,
1996, 61, 2908; A. Padwa, Z. J. Zhang and L. Zhi, J. Org. Chem., 2000,
65, 5223.
15 For the only known example of where a triflyl azide solution was used
as a diazo-transfer reagent, see: A. B. Charette, R. P. Wurz and T.
Ollevier, J. Org. Chem., 2000, 65, 9252.
6 The stereochemistry of 17a, and related compounds, have been
confirmed by X-ray crystallography, see: ref. 2 and T. Gelbrich and M.
B. Hursthouse, Acta Crystallogr., Sect. E, 2001, 57, o566.
7 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput.
Sci., 1996, 36, 746.
We thank GlaxoSmithKline for a CASE studentship (N. A.
S.) and the Royal Society for a University Research Fellowship
1
(
R. C. D. B). R. C. D. B. also thanks AstraZeneca and Merck
Sharp & Dohme for unrestricted grants and Personal Chemistry
for their generous donation of a microwave reactor. We wish to
acknowledge the use of the EPSRC’s Chemical Database
Service at Daresbury.17
1
18 N. I. Sax, Dangerous properties of industrial materials, Van Nostrand
Reinhold Company, New York, 5th edn., 1979.
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